Coronary heart disease and risk factors in NIDDM--experience from the United Kingdom Prospective Diabetes Study.
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Adult↗
Biomedical subjects
R R Holman
Publications and source records attributed to R R Holman.
The Fasting Hyperglycaemia Study: I. Subject identification and recruitment for a non-insulin-dependent diabetes prevention trial.
Subjects at increased risk for developing non-insulin-dependent diabetes mellitus (NIDDM) were encouraged via a public awareness campaign, general practitioners, or a direct approach (in the case of women with previous gestational diabetes) to attend one of three English and two French centers for fasting plasma glucose (FPG) measurement. Of 1,580 subjects (mean +/- SD age, 47 +/- 10 years), 29% were male, 56% had a diabetic relative, 20% had a history of elevated blood glucose or glycosuria, and 9% previously had gestational diabetes. Thirty-one percent (493) had an initial increased fasting glucose ([IFG] 5.5 to 7.7 mmol.L-1), 3% (41) a diabetic fasting glucose ([DFG] > or = 7.8 mmol.L-1), and 66% (1,046) a normal fasting glucose ([NFG] < 5.5 mmol.L-1). Four hundred forty-one of the 493 returned for a second FPG measurement, and 67% (293) of these had a similar value on repeat testing 2 weeks later. A 75-g, 2-hour oral glucose tolerance test (OGTT) in 223 of these subjects showed that 37% (83) had impaired glucose tolerance (IGT), 26% (58) diabetes mellitus (DM), and 37% (82) normal glucose tolerance (NGT). Seven percent of self-referred patients had NIDDM by World Health Organization (WHO) criteria. Eighty-eight percent of those with an initial DFG had an increased glycated hemoglobin (> 6.2%), and 75% an increased fructosamine (> 282 mumol.L-1). While these two glycemic measures provided good discrimination for diabetes, neither were reliable in detecting those with increased but not diabetic FPG values. In conclusion, 293 (19%) of 1,580 self-referred subjects were identified as having persistently increased FPG, and 227 have been entered into a randomized NIDDM prevention trial evaluating healthy-living advice and sulfonylurea therapy.
Adult↗
The Fasting Hyperglycaemia Study: II. Randomized controlled trial of reinforced healthy-living advice in subjects with increased but not diabetic fasting plasma glucose.
Self-referred subjects (N = 227) thought to be at risk of developing non-insulin-dependent diabetes mellitus (NIDDM) and with fasting plasma glucose (FPG) in the range of 5.5 to 7.7 mmol.L-1 on two consecutive tests 2 weeks apart were randomized to reinforced or basic healthy-living advice. They were simultaneously allocated either to a sulfonylurea group or a control group in a two-by-two factorial design. A total of 201 subjects in three English and two French centers completed 1 year's follow-up study. Reinforced advice recommending dietary modification and increased exercise was given every 3 months, and basic advice was given once at the initial visit. Glycemia was monitored by FPG, dietary compliance by body weight and food diaries, and fitness compliance by bicycle ergometer assessment and exercise diaries. Both reinforced and basic advice groups had a significant mean reduction in body weight (1.5 kg) at 3 months, although the weight subsequently returned to baseline. After 1 year, subjects allocated to reinforced advice versus basic advice (1) reported a lower fat intake (34.1% v 35.8%, P = .04) with no difference in lipid profiles, (2) had improved fitness as shown by increased calculated maximal oxygen uptake ([Vo2max] 2.39 v 2.18 L.min-1, P = .007) with no change in insulin sensitivity, (3) showed no change in FPG, glucose tolerance, or hemoglobin A1c (HbA1c), and (4) showed a greater tendency to withdraw from the study (16% v 7%, P = .03). In conclusion, reinforced healthy-living advice given to self-referred subjects with increased FPG did not encourage sufficiently pronounced life-style changes for significantly greater effects on body weight and glycemia in a 1-year study than basic healthy-living advice.
Adult↗
The Fasting Hyperglycaemia Study: III. Randomized controlled trial of sulfonylurea therapy in subjects with increased but not diabetic fasting plasma glucose.
Self-referred subjects (N = 227) thought to be at increased risk of developing diabetes who had fasting plasma glucose (FPG) values in the range of 5.5 to 7.7 mmol.L-1 on two consecutive occasions 2 weeks apart were randomized to sulfonylurea therapy (gliclazide, < or = 160 mg.d-1) or to a control group allocated either to double-blind placebo or to no tablets. Subjects were randomly allocated also to reinforced or basic healthy-living advice in a factorial design. A total of 201 subjects have been evaluated for 1 year in three English and two French hospital outpatient centers. Those allocated to sulfonylurea had a significant (P < .001) reduction in median FPG compared with the control group (6.0 mmol.L-1 to 5.6 mmol.L-1, P < .001, v 6.0 mmol.L-1 to 6.0 mmol.L-1, NS). Median hemoglobin A1c (HbA1c) also improved (P < .0002; 5.8% to 5.6%, P < .001, v 5.7% to 5.6%, NS), as did mean beta-cell function (62% to 70%, P < .01, v 62% to 61%, NS). Mean body weight was unchanged in subjects allocated to sulfonylurea (81.7 kg to 82.4 kg, NS), but decreased in the control group (81.6 kg to 80.4 kg, P < .01). More subjects in the sulfonylurea group versus the control group reported one or more minor symptoms of hypoglycemia over 1 year (50% v 24%, P < .0001). Only two subjects reported major hypoglycemic episodes requiring assistance, both of whom were taking sulfonylurea. Insulin sensitivity did not change between groups. Sulfonylurea therapy with gliclazide improved glycemic control and beta-cell function significantly in subjects with increased but not diabetic FPG levels. The study is being extended to determine whether sulfonylurea therapy prevents progression to non-insulin-dependent diabetes mellitus (NIDDM).
Adult↗
UKPDS 20: plasma leptin, obesity, and plasma insulin in type 2 diabetic subjects.
We measured plasma leptin and insulin concentrations across a spectrum of obesity in 829 white Caucasian, 154 Afro-Caribbean, and 204 Asian type 2 diabetic subjects. Although the leptin concentrations covered a large range, there were no subgroups of diabetic subjects with very high or low leptin levels that would suggest mutations in the leptin gene or leptin receptor gene comparable to the obese diabetic ob/ob and db/db mice models respectively. In all three ethnic groups, leptin concentrations correlated with body mass index (BMI) in a similar manner to nondiabetic patients and were higher in females than males after adjustment for BMI, with no difference between ethnic groups. In a multivariate regression analysis, plasma leptin was associated with gender and BMI, (both P < 1 x 10(-17)) and with fasting plasma insulin concentrations (P = 5 x 10(-9)). Subjects treated with insulin had both raised insulin and leptin concentrations. When matched for different therapies, gender, and BMI, diabetic subjects with high leptin levels also had high insulin levels (P < 0.0009). High leptin concentrations may in part be influenced by hyperinsulinemia or impaired insulin sensitivity.
Aged↗
U.K. Prospective Diabetes Study 22. Effect of age at diagnosis on diabetic tissue damage during the first 6 years of NIDDM.
OBJECTIVE: To assess the effect of age at diagnosis on the initial prevalence and subsequent risk of the progression of diabetic tissue damage in patients with NIDDM. RESEARCH DESIGN AND METHODS: The prevalence of Q-wave myocardial infarction, absent dorsalis pedis pulses, retinopathy, absent ankle jerks, hypertension, and microalbuminuria were determined at baseline and at 3 and 6 years of follow-up in five consecutive 6-year age-cohorts of 3,027 newly diagnosed white patients aged between 36 and 65 years recruited to the U.K. Prospective Diabetes Study. The effect of age at diagnosis on the initial prevalence and the risk of progression of these complications and associated conditions was analyzed using logistic regression and proportional odds methods, respectively. RESULTS: Q-wave myocardial infarction and hypertension were more prevalent in older patients at presentation, but age at diagnosis did not have a significant effect on the increased risk of either after 6 years of NIDDM. Absent dorsalis pedis pulses and ankle jerks were also more prevalent in the older age-groups at presentation, but age at diagnosis was a significant predictor of the increasing prevalence of both during follow-up. The baseline prevalence of retinopathy and microalbuminuria was not related to age. The subsequent risk of retinopathy, but not microalbuminuria, increased significantly with age at diagnosis. CONCLUSIONS: Age at diagnosis has a variable impact on different types of diabetic tissue damage and may thus be an important variable in epidemiological and intervention studies in NIDDM. Regular ophthalmologic surveillance and examination of the feet increase in importance with increasing age since the diagnosis of NIDDM.
Adult↗
Approach to maintaining comparability of biochemical data during long-term clinical trials.
Our objective was to design a structured approach to maintaining comparability of biochemical data during a long clinical trial. Maintaining the comparability of clinical and biochemical data obtained in long-term studies is essential, even though analytical methods in the laboratory may be changed, conventions on specimen handling and storage revised, calibration procedures updated, quality-control systems replaced, and secular changes may occur. The United Kingdom Prospective Diabetes Study (UKPDS), a large randomized control trial investigating therapy for type 2 diabetes, was the setting for the study. Data were collected from 5102 subjects randomized since 1977. Our techniques included quality control, external quality assurance, direct comparison of laboratory methods when updating assays and statistical techniques for the detection of unsuspected changes in assay bias, laboratory comparisons of new with old assay methodologies, the realigning of data to current methods, the use of a suitable reference population for long-term monitoring, and rules to aid decision-making about clinical vs statistical significance. Procedures by which comparability of data is assured should be specified for all long-term trials and, where possible, comparison with reference methods should be detailed to allow results from different laboratories to be compared.
Diabetes Mellitus, Type 2↗
UKPDS 18: estimated dietary intake in type 2 diabetic patients randomly allocated to diet, sulphonylurea or insulin therapy. UK Prospective Diabetes Study Group.
Self-reported dietary intake was estimated from 3-day prospective food diaries completed by Type 2 diabetic patients in the UK Prospective Diabetes Study. All patients had received individual dietary advice and had been randomly allocated to diet, sulphonylurea or insulin therapy 3 months after diagnosis. A total of 132 patients (120 white Caucasian, 12 Asian) stratified for gender, obesity and allocated therapy with mean age 55 years (SD 8), body mass index 28 kg m-2 (SD 4), and with a diabetes duration of 3 to 6 years were selected at random from 5 of 23 clinical centres. Patients reported a similar proportion of their energy intake as carbohydrate (43%) to the general population and had not increased to the recommended 50-55%. Their protein intake (21%) was higher than the advised 10-15%. Estimated energy intake from fat (37%) was close to that recommended for diabetic patients (30-35%) and was lower than that reported for the UK population (40%). The estimated polyunsaturated/saturated fat intake ratio (0.48) was higher than that reported for the UK population (0.35) compared with the recommended 1.0. Mean fibre intake at 22 g day-1 was less than the recommended 30 g day-1. The 8 male Asian patients took a higher proportion of their dietary intake as fat (46% vs 37%) and lower as protein (14% vs 21%) than the male white Caucasian patients. No significant differences were seen in estimated nutrient constituents between patients allocated to diet, sulphonylurea or insulin therapy as part of the UK Prospective Diabetes Study and followed for mean 4.2 years (SD1.6). This suggests that dietary factors will not confound UK Prospective Diabetes Study treatment related analyses.
Cross-Sectional Studies↗
High prevalence of a missense mutation of the glucokinase gene in gestational diabetic patients due to a founder-effect in a local population.
A high proportion of the female patients who are members of maturity onset diabetes of the young (MODY) pedigrees, and whose diabetes mellitus is due to a glucokinase mutation, originally presented with gestational diabetes. To establish whether glucokinase mutations could be a common cause of gestational diabetes, we studied 50 subjects who presented with gestational diabetes and on follow-up had hyperglycaemia (5.5-10.0 mmol/l). Screening for glucokinase mutations using single-stranded conformational polymorphism (SSCP) analysis detected a missense mutation at position 299 (Gly299-->Arg) in three subjects. As two pedigrees in the Oxford area had the same glucokinase mutation, we suspected the role of a founder-effect, and carried out pedigree extension, haplotype construction (using microsatellite markers GCK1 and GCK2) and mutation screening of at-risk subjects from the same geographical area. One of the gestational diabetic subjects was found to be related to one of the previous pedigrees via her paternal grandmother. Subjects with the mutation were found to have the Z + 4/2 (GCK1/ GCK2) haplotype, suggesting that the observed high prevalence of the Gly299-->Arg glucokinase mutation in the Oxford region was due to a founder-effect. Since glucokinase mutations predominantly induce subclinical hyperglycaemia, it is likely that in the locality of other pedigrees there will be undiagnosed subjects with the same glucokinase mutation, which remains undetected unless pregnancy occurs.
Adult↗
U.K. prospective diabetes study.
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Blood Glucose↗
The UK Prospective Diabetes Study. UK Prospective Diabetes Study Group.
The Diabetes Control and Complications Study has shown that improved blood glucose control would delay the progress of microvascular complications of diabetes. However, in patients with non-insulin-dependent diabetes mellitus, the major morbidity and mortality arises from premature cardiovascular disease. It is uncertain whether therapy aimed to improve diabetes control will prevent cardiovascular complications, and whether the available therapies, sulphonylurea, biguanides or insulin, may even have long-term deleterious side-effects. The UK Prospective Diabetes Study started in 1977 and is evaluating whether long-term therapy to improve glucose control would be advantageous in clinical practice. The study has demonstrated that it is difficult to maintain improved glucose control because of the progressive beta-cell dysfunction. The study is also evaluating whether improved control of hypertension would be advantageous. The progress of the study is summarized. The results are expected to be published in 1998.
Adult↗
Frequency of hypoglycemic episodes during intensive therapy with human insulin.
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Blood Glucose↗
UK prospective diabetes study (UKPDS) 14: association of angiotensin-converting enzyme insertion/deletion polymorphism with myocardial infarction in NIDDM.
The deletion allele of the insertion/deletion polymorphism of the angiotensin-converting enzyme gene has been suggested to be an independent risk factor for myocardial infarction, particularly in subjects judged to be "low-risk" by the criteria of lipid status and body mass index. In a prospective, matched case-control study, we have investigated the role of this polymorphism as a risk factor for myocardial infarction in 173 newly-diagnosed British Caucasian non-insulin-dependent diabetic subjects taken from the United Kingdom Prospective Diabetes Study who subsequently developed myocardial infarction and 297 control subjects from the same study population matched for known cardiovascular risk factors including age at diagnosis of diabetes, gender, blood pressure, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride and smoking habit. A trend towards increased risk conferred by homozygosity for the deletion allele was observed in cases (odds ratio 1.63, p = 0.09). When the population was stratified according to the matched risk factors, the deletion allele was associated with myocardial infarction in those with low plasma low-density lipoprotein cholesterol (odds ratio 3.67, p = 0.002), or low triglyceride (odds ratio 3.14, p = 0.005). The strongest association of the deletion allele with myocardial infarction was observed in subjects with both low low-density lipoprotein cholesterol and low triglyceride levels (odds ratio 9.0, p < 0.001). These results show that the deletion allele is a risk factor for myocardial infarction in non-insulin-dependent diabetic patients who have a favourable lipid profile.
Case-Control Studies↗
Insulin therapy in type II diabetes.
When diet therapy is no longer effective in keeping the fasting plasma glucose level < 6 mmol l-1, a basal insulin supplement from a long-acting insulin such as ultralente can be added instead of using a sulphonylurea or metformin. The dose of insulin required can be predicted from the level of the fasting plasma glucose and the degree of obesity, which provides an index of the accompanying insulin resistance. The risk of hypoglycaemia is minimal provided that the dose is adjusted according to the fasting plasma glucose concentration and the patient can continue a normal life-style without restrictions concerning exercise or the size of individual meals. If given in appropriate doses a basal insulin supplement does not induce marked weight gain and insulin therapy is equally appropriate in patients with insulin deficiency and insulin resistance. Maintaining near-normal glucose concentrations probably outweights a putative risk of hyperinsulinaemia. In more severely affected patients, such as those with sulphonylurea failure, soluble insulin to cover meals in addition to a basal insulin supplement is needed. At this stage it is usual to stop tablet therapy and treat patients with either a basal and prandial insulin regimen or with twice daily soluble and isophane mixtures. Nevertheless, in elderly patients in whom regular meals cannot be guaranteed, continuing with sulphonylurea therapy and adding a basal insulin supplement can be a safe and effective way of preventing hyperglycaemic symptoms.
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Lessons from UK prospective diabetes study.
Type II diabetes is a major cause of morbidity and mortality, both from an increased risk of developing cardiovascular disease and from specific diabetic complications. At present, patients are often treated to prevent marked hyperglycaemia, that induces symptoms such as thirst. Moderately raised glucose levels are then accepted. At present, it is uncertain whether Type II diabetes should be treated more intensively, with diet, tablet or insulin therapy to maintain near-normal glucose levels, in order to prevent the onset of complications. The Diabetes Control and Complications Trial (DCCT) in insulin-dependent diabetic subjects with a mean age of 27 years has indicated that intensive therapy to achieve a haemoglobin A1c level of 7.1%, compared with 9.0% in a 'standard control group', will retard the progress of diabetic microvascular disease. It is not known whether this is similarly beneficial in Type II diabetic subjects, where the main complication is cardiac disease, or whether the even better control that can be obtained with pharmaceutical therapy in Type II diabetic patients would be worthwhile. It is similarly not known whether treatment with sulphonylurea, metformin or insulin is particularly beneficial or whether any of these therapies is potentially harmful. The UK Prospective Diabetes Study (UKPDS) has randomly allocated 4209 newly diagnosed Type II diabetic patients to different therapies and is determining: (a) whether improved glucose control will delay the onset of clinical complications; and (b) whether any specific therapy has advantages or disadvantages.
Adult↗
[The UKPDS study on glycemic control and arterial hypertension in type II diabetes: objectives, structure and preliminary results].
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Adult↗
Post-prandial glycaemic reduction by an alpha-glucosidase inhibitor in type 2 diabetic patients with therapeutically attained basal normoglycaemia.
Post-prandial glucose excursions remain elevated in most patients with diabetes even when normal fasting plasma glucose levels have been achieved. In 39 patients with type 2 diabetes who had attained basal normoglycaemia by therapy with diet alone, a sulphonylurea, a basal insulin supplement or basal plus prandial insulin the mean glycosylated haemoglobin (HbA1) values were at the upper end (mean +/- 1SD, 8.1 +/- 1.1%) of the normal range (5.0-8.2%). Miglitol, an alpha-glucosidase inhibitor, given in a dose of 50 mg three times a day was studied in a double blind randomized crossover study. In diet and sulphonylurea treated patients, a mean 25% reduction of the post-prandial plasma glucose excursions was obtained whereas in ultralente treated patients miglitol appeared to reduce basal plasma glucose levels (p < 0.006). Side effects were limited to minor gastrointestinal disturbances, usually ameliorating after the first week of therapy. Alpha-glucosidase inhibition to prevent post-prandial glycaemia may have a role in patients in whom sulphonylurea or diet therapy has been used to obtain normal basal glucose concentrations.
1-Deoxynojirimycin↗
Insulin use in NIDDM. Rationale based on pathophysiology of disease.
Because basal hyperglycemia is a major feature in non-insulin-dependent diabetes mellitus, diabetes control can be monitored by the fasting blood glucose concentration. A hierarchical sequence of therapies is proposed in which the major aim is to maintain near-normal fasting blood glucose concentrations, in the expectation that this will help prevent development of long-term complications. When diet and tablet therapy are no longer effective in keeping the fasting blood glucose level less than 6 mM, a basal insulin supplement from a long-acting insulin such as ultralente can be added. When monitored by fasting blood glucose concentration, there is little risk of hypoglycemia, and the patient can continue a normal life-style without restrictions concerning exercise or the size of individual meals. A basal insulin supplement does not induce marked weight gain. The dose of insulin required can be predicted from the level of the fasting blood glucose and the degree of obesity, which provides an index of the accompanying insulin resistance. Based on current evidence, insulin therapy is equally appropriate in patients with insulin deficiency and insulin resistance, because the benefit from maintaining near-normal glucose concentrations probably outweighs a putative risk of hyperinsulinemia. In more severely affected patients, additional regular insulin to cover meals is needed. Lowering fasting blood glucose to normal with a basal insulin supplement reduces endogenous insulin production, and this may be advantageous if accompanying production of islet amyloid polypeptide and islet amyloid formation are also reduced.
Diabetes Mellitus, Type 2↗