Preservation of physiological responses to hypoglycemia 2 days after antecedent hypoglycemia in patients with IDDM.

OBJECTIVE: To assess the effects of short-term antecedent hypoglycemia on responses to further hypoglycemia 2 days later in patients with IDDM. RESEARCH DESIGN AND METHODS: We studied eight type I diabetic patients without hypoglycemia unawareness or autonomic neuropathy during two periods at least 4 weeks apart. On day 1, 2 h of either clamped hyperinsulinemic (60 mU.m-2.min-1) hypoglycemia at 2.8 mmol/l or euglycemia at 5.0 mmol/l were induced. Hyperinsulinemic hypoglycemia was induced 2 days later with 40 min glucose steps of 5.0, 4.0, 3.5, 3.0, and 2.5 mmol/l. Catecholamine levels and symptomatic and physiological responses were measured every 10-20 min. RESULTS: When compared with the responses measured following euglycemia, the responses of norepinephrine 2 days after hypoglycemia were reduced (peak, 1.4 +/- 0.4 [mean +/- SE] vs.1.0 +/- 0.3 nmol/l [P < 0.05]; threshold, 3.4 +/- 0.1 vs. 2.9 +/- 0.1 mmol/l glucose [P < 0.01]). The responses of epinephrine (peak, 4.0 +/- 1.4 vs. 3.5 +/- 0.8 nmol/l [P = 0.84]; threshold, 3.8 +/- 0.1 vs. 3.6 +/- 0.1 mmol/l glucose [P = 0.38]), water loss (peak, 194 +/- 34 vs. 179 +/- 47 g-1.m-2.h-1 [P = 0.73]; threshold, 2.9 +/- 0.2 vs. 2.9 +/- 0.2 mmol/l glucose [P = 0.90]), tremor (peak, 0.28 +/- 0.05 vs. 0.37 +/- 0.06 root mean square volts (RMS V) [P = 0.19]; threshold, 3.2 +/- 0.2 vs. 3.1 +/- 0.2 mmol/l glucose [P = 0.70]), total symptom scores (peak, 10.6 +/- 2.1 vs. 10.8 +/- 1.9 [P = 0.95]; threshold, 3.3 +/- 0.2 vs. 3.6 +/0 0.1 mmol/l glucose [P = 0.15]), and cognitive function (four-choice reaction time: threshold, 2.9 +/- 0.2 vs. 3.0 +/- 0.2 mmol/l glucose [P = 0.69]) were unaffected. CONCLUSIONS: The effect on hypoglycemic physiological responses of 2 h of experimental hypoglycemia lasts for 1-2 days in these patients with IDDM . The pathophysiological effect of antecedent hypoglycemia may be of shorter duration in IDDM patients, compared with nondiabetic subjects.

Dynamic foot pressure and other studies as diagnostic and management aids in diabetic neuropathy.

The pressures and loads under the feet during walking have been compared in three groups of 41 patients each, using a microprocessor-controlled optical system. Group A consisted of patients with diabetic neuropathy, group B of non-neuropathic diabetic patients, and group C of nondiabetic controls. Thirteen patients in group A had a history of neuropathic foot ulceration. Other investigations in the diabetic patients included motor conduction velocity (MCV) in the median and peroneal nerves, vibration perception threshold (VPT) in the great toes, the valsalva response (VR), skin resistance (SR), and the ankle pressure index (API). Fifty-one percent of neuropathic feet had abnormally high pressures underneath the metatarsal heads compared with 17% of the diabetic controls and 7% of nondiabetic subjects. All those feet with previous ulceration had abnormally high pressures at the ulcer sites. Of the other investigations, the VPT correlated most significantly with the presence of foot ulceration. In addition, a low median and peroneal nerve MCV, an abnormal VR, a high API, and the absence of sweating all correlated with the presence of foot ulceration. We therefore conclude that simple bedside investigations, such as measurement of the VPT alone, may be useful in identifying those patients at risk of foot ulceration. Foot pressure studies may then be used in such patients as a predictive and management aid by determining specific areas under the foot that are prone to ulceration.

Analysis of antibodies against components of the autonomic nervous system in diabetes mellitus.

Antibodies to autonomic nervous system structures have previously been detected using a complement fixation immunofluorescence test in the sera of patients with insulin-dependent diabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus (NIDDM). These antibodies might play a role in the aetiology of autonomic neuropathy. Sera from 45 IDDM, 40 NIDDM and 52 control subjects were tested by immunofluorescence for antibodies to human sympathetic ganglia, human adrenal medulla and rabbit vagus nerve. The use of human sympathetic ganglia was compared with rabbit tissue for the detection of sympathetic ganglia antibodies; the results for these autonomic nervous system antibodies were also compared with results using an ELISA. There was no relationship between the presence of antibodies detected by ELISA and those detected by immunofluorescence, but of 14 IDDM patients with thyroid antibodies, 12 had autonomic nervous system antibodies detected by either immunofluorescence or ELISA (p < 0.005 compared to patients without thyroid antibodies). To further characterize the autoantigen(s), immunoblotting was performed. An adrenal antigen corresponding to 74 kDa was detected in sera from three patients, only one of whom had antibodies detectable by ELISA and immunofluorescence. One IDDM serum showed specific binding to a vagus nerve antigen corresponding to 33 kDa. No specific binding to sympathetic ganglia antigen was demonstrated. Antibodies against autonomic nervous system antigens are an inconsistent feature of diabetes, and appear more associated with coincidental autoimmunity against other organs such as the thyroid.

Chromium homeostasis in patients with type II (NIDDM) diabetes.

The purpose of this study was to assess chromium handling in non-insulin dependent diabetic patients (NIDDM) compared to healthy volunteers. Chromium handling was evaluated using fasting blood and second morning void urine samples from 93 NIDDM patients and 33 healthy volunteers. Significant differences in chromium homeostasis were seen between patients and controls. NIDDM patients had mean levels of plasma chromium around 33% lower and urine values almost 100% higher than those found in health. Healthy volunteers showed a significant negative correlation between fasting levels of plasma chromium and insulin. This was not evident in NIDDM patients. In the early years of onset of NIDDM, plasma chromium values were inversely correlated with plasma glucose. This was lost in patients with diabetes of more than 2 years duration. We suggest large losses of chromium over many years may exacerbate an already compromised chromium status in NIDDM patients and might contribute to the developing insulin resistance seen in patients with type 2 diabetes.

Novel role for specialist nurses in managing diabetes in the community.

To develop care of diabetes further a specialist nurse established contact with general practices in Sheffield Health District and identified difficulties in providing a service for diabetics. One hundred and thirty practices were visited, and full data were collected from 104. Each practice agreed to establish a register of diabetics, and information and support were subsequently provided to help in developing services. In collecting information from each practice the nurse covered specific points on staff, facilities, and organisation. Over two years the service offered in 60 practices considerably improved, allowing a minimum standard of diabetic care to be achieved. This allowed coordinated and effective referral of certain patients from hospital diabetic clinics and improved services to those not attending any clinics.

Early onset type 2 diabetes mellitus: a harbinger for complications in later years--clinical observation from a secondary care cohort.

BACKGROUND: Little is known about the complication burden in later years among early onset type 2 diabetes mellitus (T2DM). AIM: To determine the magnitude of diabetes complications and adequacy of risk factor management and to test the hypothesis that diabetes duration is an important contributing factor to these complications. DESIGN: A cross-sectional study of secondary care diabetes population. METHODS: Data on glycaemic control, cardiovascular risk factors (overweight/obesity, hypertension, dyslipidaemia), cardiovascular disease (CVD) and microvascular complications among those diagnosed before (early onset) and after (later onset) 40 years of age at different diabetes durations (<10, 10-20 and >20 years) were analysed. RESULTS: A total of 2733 subjects were identified, of which 527 had diabetes diagnosed below the age of 40 years. By the sixth decade of life, early onset cohort experienced high complication burden (CVD: 37.2%, retinopathy: 59.3% and neuropathy: 53.1%). Complication prevalence increased with diabetes duration but the increment rate was greater among early onset cohort. Compared with those diagnosed after 40, early onset cohort experienced similar burden of microvascular complications approximately 13-20 years earlier. Diabetes duration was a significant predictor for microvascular and CVD complications. Prevalence of CVD risk factors was high ( approximately 80-93%) regardless of the age of diagnosis and diabetes duration. Early onset subjects were more likely to have poorer glucose control ( approximately 70-78%), untreated hypertension (26.3%) and a substantial number did not receive statin treatment for primary prevention (34.8%). DISCUSSION: Early onset T2DM subjects are at substantial risk of developing diabetes complications in later years but at an earlier stage than later onset cohort and prolonged exposure to adverse diabetic milieu is an important contributing factor. Management of risk factors for diabetes complications was inadequate among early onset subjects.

Type 2 diabetes mellitus: a high-risk condition for cardiovascular disease irrespective of the different degrees of obesity.

BACKGROUND: Measurement of body weight with body mass index (BMI) is often utilized to stratify cardiovascular disease (CVD) risk. AIM: To determine CVD risk profile and disease burden in subjects with type 2 diabetes mellitus (T2DM) across different categories of body weight as defined by BMI. DESIGN: Prospective observational study. METHODS: CVD risk including metabolic syndrome (MetS) and prevalence of macrovascular complications were determined for each category of body weight as defined by the World Health Organisation (WHO) classification. RESULTS: A total of 390 subjects were included in this study of which 35.9% were non-obese (BMI <30 kg/m(2)). Although increasing obesity as defined by BMI was associated with higher prevalence of central abdominal obesity, hypertension and MetS (P < 0.05), dyslipidaemia and macrovascular complications were not significantly different across the various body weight categories (P = NS). Similar observation was seen in non-obese (BMI <30 kg/m(2)) and obese subjects (BMI >30 kg/m(2)). Among non-obese (including normal weight) cohort, the majority of these subjects had adverse CVD risk profile including presence of at least two co-existing risk factors. CONCLUSION: Subjects with T2DM possess adverse CVD risk factors with significant burden of macrovascular disease irrespective of their baseline body weight.

Diagnosing metabolic syndrome in type 2 diabetes: does it matter?

BACKGROUND: Metabolic syndrome (MetS) is used as a clinical tool to identify individuals at risk of cardiovascular disease (CVD) but its clinical value in the management of type 2 diabetes mellitus (T2DM) remains uncertain. AIM: To determine the prevalence and clinical usefulness of MetS among patients with T2DM attending diabetes clinics in a large teaching hospital. DESIGN: Prospective observational study. METHODS: Prevalence of MetS was determined by using International Diabetes Federation (IDF) and National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATPIII) definitions in relation to age, sex, diabetes duration and history of CVD. RESULTS: A total of 390 patients were included in this study. Both IDF and NCEP-ATPIII definitions identified high prevalence of MetS in male and female patients (IDF: male vs. female, 91.7 vs. 94.8% and NCEP-ATPIII: male vs. female, 87.6 vs. 94.2%) regardless of age (below vs. above 40 yrs, approximately 70-75 vs. approximately 90-95% with both definitions), diabetes duration (below vs. above 5 yrs, approximately 85-90 vs. 90-95% with both definitions) and history of CVD (without vs. with CVD, approximately 90 vs. approximately 95% with both definitions). Central obesity was common reflected by mean waist circumference of approximately 113 cm regardless of age and gender. Among those who did not have IDF-defined MetS, approximately 60% had at least two CVD risk factors. Both definitions similarly classified approximately 94% of the patients as either having or not having MetS. DISCUSSION: Both definitions can be used interchangeably to diagnose MetS. However, the clinical usefulness of MetS is debatable given the very high prevalence of this condition in T2DM.

Serum long acting thyroid stimulator protector in pregnancy complicated by Graves' disease.

Activities of serum long acting thyroid stimulator protector were measured in a series of nine pregnancies in eight mothers who had Graves' disease, one of whom had been successfully treated by surgery. In all but two instances the activities tended to decline as pregnancy progressed. After delivery activities rose in three out of five patients in whom these had disappeared in pregnancy and, as this occurred, the patients relapsed. In the two patients whose activities did not decline thyrotoxicosis persisted throughout pregnancy and after delivery. None of the nine babies in this study suffered from neonatal thyrotoxicosis because maternal activities of the thyroid stimulator protector, though high enough to induce Graves' disease in adults, were not above the threshold for the induction of thyroid overactivity in neonates.

Perioperative antibiotic prophylaxis and prosthetic valve endocarditis.

A study of twenty-five cases of prosthetic valve endocarditis suggests that the antibiotics used for perioperative prophylaxis may alter the type and antibiotic sensitivity of organisms which subsequently infect the artificial valves. Based on the results of this study, the authors have been able to modify their prophylactic regime to encompass these organisms and to predict the antibiotics most likely to be effective in the treatment of prosthetic valve endocarditis in their unit. No single prophylactic or therapeutic regime will be equally effective in all centres, but by examining the different types and sensitivities of bacteria which cause prosthetic valve endocarditis in a locality, antibiotic regimes can be chosen which best suit the local situation.

The effect of partial thyroidectomy for Graves' disease on serum long-acting thyroid stimulator protector (LATS-P).

The effect of partial thyroidectomy on serum LATS-P has been investigated in twenty-one consecutive patients. Before surgery, LATS-P was detectable in seventeen (81%) but 1 year after operation only five (24%) had activity. The activity did not fall immediately after surgery but declined progressively throughout the year. In no patient was an increase in activity demonstrated; nor did LATS-P appear in those patients who did not have activity before operation.

Pericardial effusion in hypothyroidism.

Thirty-nine patients with untreated hypothyroidism have been examined using echocardiography for the presence of a pericardial effusion. Effusions were present in twelve patients who tended to be more severely hypothyroid. Plasma creatine phosphokinase and lactate dehydrogenase levels were higher in the presence of an effusion. Nine were reinvestigated during thyroxine replacement therapy and the effusions did not disappear until thyroid function tests had returned to normal. There were no specific electrocardiographic changes associated with the presence of an effusion which could be associated with a normal cardiac silhouette on a standard P.A. chest X-ray.

The prediction of relapse after drug treatment of Graves' disease by assay of long acting thyroid stimulator-protector (LATS-P).

In a study of fifty-two patients with Graves' disease followed for 1 year after stopping antithyroid drugs, a strong relationship has been found between serum LATS-P and relapse. In those with serum LATS-P activity on stopping therapy, twenty-one (88%) out of twenty-four relapsed. In those with no LATS-P activity on stopping antithyroid drugs only eight (29%) out of twenty-eight relapsed and in five LATS-P was detectable at relapse. The overall prevalence of positive assays for LATS-P at relapse (90%) was similar to that seen in untreated Graves' disease.

Serum long acting thyroid stimulator (LATS) and LATS-protector (LATS-P) in Graves' disease associated with localized myxedema.

When localized myxedema occurs in Graves' disease, there is often very high serum long acting thyroid stimulator (LATS) activity. However, this association is not invariable and no pathogenetic role for this IgG associated activity is known. Serum LATS protector (LATS-P) is a closely related IgG activity which is present in the majority of cases of untreated Graves' disease. It usually coexists in LATS positive sera in a substantially greater concentration. Its association with localized myxedema has not been studied, nor have serial studies been performed on this activity during the clinical course of the disease. Fourteen patients (13 females, 1 male) with localized myxedema and a history of Graves' disease were examined. In 13 serum LATS was detectable with a wide range of activity from 2.4 to 1,000 units/ml. Serum LATS-P was detected in all including the LATS negative patient with a range of activity from 46 to 4,068 units/ml. Serial studies for at least 2 years were conducted in 8 patients. In two there was no change in either skin lesions or in serum LATS and LATS-P. In 6 the skin lesions partially or completely resolved. In 5 this was associated with statistically significant falls in serum LATS and LATS-P but in one no significant change occurred. The study demonstrated the high prevalence of LATS and LATS-P in localized myxedema. In the sole LATS negative patient there was a high concentration of LATS-P. The role of these activities in the pathogenesis of the disease remains unknown but in serial studies falls in activity were usually associated with clinical improvement.

The effect of radioiodine and antithyroid drugs on serum long acting thyroid stimulator protector (IATS-P). A three year prospective study.

Over a three year period we have studied the effect of either a one year course of Carbimazole or a single dose of radioiodine in a group of 46 patients with Graves' disease. Initially, in untreated patients LATS-P was present in 39 (85%) but at the end of the study was only detectable in 19 (41%). The clinical outcome in 29 patients initially treated with carbimazole correlated well with changes in serum LATS-P which persisted in 18. Thirteen of these ultimately required radioiodine or sub-total thyroidectomy. With radioiodine two patterns of response were seen, in some LATS-P levels declined, whereas in others transient increases were seen usually during the first year but subsequently fell. There was no difference in clinical response between the two groups. Overall, the study indicates that serum LATS-P is related to the clinical course of Graves' disease but there remains a minority of patients in whom the activity cannot be detected.

Long-acting thyroid stimulator (LATS) and long acting thyroid stimulator protector (LATS-P) in untreated thyrotoxicosis.

The prevalence of serum LATS and LATS-P in untreated Graves' disease has been studied in eighty-three patients with thyroid overactivity; twelve (14%) were found to have significant levels of LATs and LATS-P whilst fifty-nine (72%) had significant levels of LATS-P alone. Twelve (14%) had neither activity. There was a very wide range in both activities. LATS was invariably found in association with a significantly greater concentration of LATS-P. There was no correlation between LATS-P and thyroid mass, as estimated from scintiscanning, thyroidal radioiodine uptake at 4 and 48 h, total serum T4 and total serum T3. Neither LATS nor LATS-P were detected in eleven patients with toxic multinodular goitre nor four with solitary toxic adenoma.

Further evidence for a high incidence of nocturnal hypoglycaemia in IDDM: no effect of dose for dose transfer between human and porcine insulins.

We tested the hypothesis that transfer from porcine to human insulin causes a fall in nocturnal blood glucose and an increase in the frequency of hypoglycaemic episodes. Twenty IDDM patients (age 19-55, duration 3-36 years) used Velosulin and Insulatard twice daily for 12 weeks, double-blinded to species (human (H) or porcine (P)) in a randomized crossover study. Species was changed after 4 weeks' run-in and 4 weeks later, with insulin doses unchanged on transfer. Ten patients underwent each sequence (H/P/H or P/H/P) and were admitted on the first and eighth night after transfer for hourly blood glucose measurement (22.00-07.00). Biochemical hypoglycaemia (<3.5 mmol l(-1)) was observed on 39 of the 80 patient-nights studied (48.75%). The number of episodes were similar during each night (H1 8, H8 10, P1 10, P8 11, p = 0.83). Total reported symptomatic episodes (H 51 vs P 73, p = 0.85), total HbA1 (H 9.8 +/- 0.3%, P 10.0 +/- 0.3%, p = 0.32) and daily insulin doses (H 0.63 +/- 0.04 units kg(-1) day(-1) vs P 0.63 +/- 0.05 units kg(-1) day(-1), p = 0.54) were not different. Despite an apparent fall in blood glucose levels from night 1 to 8 on transfer to human (AUC 82.3 +/- 7.8 vs 61.4 +/- 5.3 mmol.h l(-1), p < 0.05) but not porcine insulin (AUC 70.7 +/- 7.2 vs 70.1 +/- 7.5 mmol.h l(-1), p = 0.74), there was no difference when all 4 nights were considered together (p = 0.30). We conclude that dose for dose transfer to human insulin does not increase numbers of episodes of nocturnal or reported hypoglycaemia.