[The UKPDS study on glycemic control and arterial hypertension in type II diabetes: objectives, structure and preliminary results].
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Adult↗
Biomedical subjects
J C Levy
Publications and source records attributed to J C Levy.
'Healthy living' and sulphonylurea therapy have different effects on glucose tolerance and risk factors for vascular disease in subjects with impaired glucose tolerance.
This study was undertaken to determine whether impaired glucose tolerance and associated risk factors for cardiovascular disease can be improved with 'healthy living' by diet and exercise or with sulphonylurea therapy. Patients were recruited by screening subjects with either a family history of type II diabetes, previous gestational diabetes, or a previously raised plasma glucose (5.6-6.6 mmol/l). Impaired glucose tolerance was defined as hyperglycaemia on two separate tests, an achieved glucose level after a glucose infusion test above the 90th percentile of an age-matched normal population (> 9.3 mmol/l) or a fasting plasma glucose above the 95th percentile (> 5.6 mmol/l). Thirty-seven subjects with impaired glucose tolerance were entered into a randomized, prospective study for 6 months with allocations to healthy living or double blind to sulphonylurea (gliclazide 40 mg twice daily) or placebo tablets. The study took place in an out-patient setting, with three times weekly exercise sessions at a Sports Centre. After 6 months the placebo group showed no change in plasma glucose, cholesterol and blood pressure. The subjects receiving gliclazide showed improved glucose levels (mean fasting plasma glucose levels fell from 5.8 to 5.1 mmol/l, p < 0.05) but no significant change in plasma cholesterol or blood pressure. The healthy living group, after exclusion of four non-compliant subjects, showed no change in glucose levels, but a decreased systolic blood pressure (fall in mean from 124 to 116 mmHg, p < 0.05) and plasma cholesterol levels (fall in mean from 5.2 to 4.5 mmol/l, p < 0.01). with an increase in HDL:LDL ratio (rise in mean from 0.39 to 0.46, p < 0.05). Subjects with impaired glucose tolerance may benefit in different ways from gliclazide and healthy living. The metabolic responses to each therapy may help to decrease the risk of developing diabetes and cardiovascular disease.
Adolescent↗
The potent 5-HT3 receptor antagonist (R)-zacopride labels an additional high affinity site in the central nervous system.
The binding characteristics of [3H](R)- and [3H](S)-zacopride were investigated in membranes from the rat entorhinal cortex and NG 108-15 clonal cells. In contrast to [3H](S)-zacopride which bound solely to 5-HT3 receptors, [3H](R)-zacopride recognized another class of binding sites, called the (R)-sites, in both membrane preparations. In addition to (R)-zacopride (Ki = 3-11 nM), only (R)-iodo-zacopride, (R)-dechloro-zacopride, prazosin and mianserin exhibited high to moderate affinity for the (R)-sites, whose possible functions remain to be established.
Animals↗
Immunoradiometric assay of insulin, intact proinsulin and 32-33 split proinsulin and radioimmunoassay of insulin in diet-treated type 2 (non-insulin-dependent) diabetic subjects.
Plasma insulin, intact proinsulin and 32-33 split proinsulin measured by specific immunoradiometric assays and insulin and C-peptide measured by radioimmunoassay were measured during a constant infusion of glucose test in ten diet-treated subjects with a history of Type 2 (non-insulin-dependent) diabetes (termed diabetic subjects), mean fasting plasma glucose 6.0 +/- 1.0 mmol/l (mean +/- SD), and 12 non-diabetic control subjects. Immunoreactive insulin concentrations measured by radioimmunoassay were 33% higher than insulin and 16% higher than the sum of insulin and its precursors by immunoradiometric assay. The diabetic and non-diabetic subjects had similar fasting concentrations of insulin, intact proinsulin and 32-33 split proinsulin. The ratio of fasting intact proinsulin to total insulin was greater in the diabetic than the non-diabetic group 12.0% (6.8-21.0%, 1 SD range) and 6.3% (4.0-9.8%), respectively, p less than 0.01), though the groups overlapped substantially. After glucose infusion, diabetic and non-diabetic subjects had similar intact proinsulin concentrations (geometric mean 4.9 and 5.2 pmol/l, respectively), but the diabetic group had impaired insulin secretion by immunoradiometric assay (geometric means 55 and 101 pmol/l, p less than 0.05) or by radioimmunoassay C-peptide (geometric means 935 and 1410 pmol/l, p less than 0.05), though not by radioimmunoassay insulin (87 and 144 pmol/l, p = 0.12), respectively. Individual immunoradiometric assay insulin responses to glucose expressed in terms of obesity were subnormal in nine of ten diabetic subjects. Radioimmunoassay insulin and C-peptide gave less complete discrimination (subnormal responses in six of ten and eight of ten, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Blood Glucose↗
Elevated plasma concentrations of beta-cell tropin (ACTH22-39) in diet-treated type II diabetic patients.
beta-Cell tropin, the pituitary peptide ACTH22-39, is a potent insulin secretagogue and stimulates lipogenesis in adipose tissue in rodents. Plasma beta-cell tropin was measured fasting and after glucose infusion (5 mg.kg glucose ideal body weight-1.min0-1 for 90 min) in 10 mild diet-treated non-insulin-dependent (type II) diabetic subjects and 10 control subjects (body mass index) (BMI): 26.4 +/- 3.2 and 24.1 +/- 2.0 kg/m-2, NS, fasting plasma glucose 7.8 +/- 2.7 mM and 4.7 +/- 0.3 mM, respectively). The diabetic subjects had raised fasting plasma beta-cell tropin compared with the normal subjects (geometric mean (1 SD range): 0.49 (0.25-0.96) nM and 0.17 (0.10-0.28) nM, respectively, P = 0.007). In response to the glucose infusion, plasma glucose rose higher in the diabetic subjects (mean +/- 1 SD: 13.7 +/- 3.1 and 9.6 +/- 0.9 mM, P = 0.007) and plasma insulin was impaired in the diabetic compared with the nondiabetic subjects (geometric mean (1 SD range): 14 (8-26) and 34 (18-63), P less than 0.01). beta-Cell tropin concentrations in the diabetic subjects rose to 1.31 (0.74-2.30) nM (P = 0.007), whereas beta-cell tropin did not change in the normal subjects at 0.19 (0.11-0.91) nM. There was no overlap between glucose-stimulated plasma beta-cell tropin in the two groups (P = 0.0002). Pituitary-adrenal function, as assessed by plasma cortisol, did not differ between the two groups when fasting and did not change after the glucose infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenocorticotropic Hormone↗
No glucotoxicity after 53 hours of 6.0 mmol/l hyperglycaemia in normal man.
In vitro and in vivo studies have suggested that metabolic deterioration can be induced by hyperglycaemia per se. The effect of 53 h of 2.2 mg glucose.kg ideal body weight-1.min-1 was examined in four normal male subjects. This produced overnight hyperglycaemia of 6.0 mmol/l on the two nights of the study compared with 4.7 mmol/l on the control night (p less than 0.05). In response there was a sustained, two-fold increase in basal plasma insulin (p less than 0.005) and C-peptide (p less than 0.05) levels. After two days of hyperglycaemia an increased Beta-cell response was demonstrated in response to an additional glucose infusion stimulus (estimated Beta-cell function median of 84% on the control day to 100% after two days glucose infusion). Plasma insulin and C-peptide responses to a 10.0 mmol/l hyperglycaemic clamp increased over the two days of the study (insulin from median 48 mU/l to 73 mU/l and C-peptide from median 2.0 pmol/ml to 2.6 pmol/l). Glucose tolerance to the additional glucose infusion stimulus improved, suggesting that the increased insulin response during hyperglycaemia was enhancing peripheral glucose uptake. The calculated peripheral insulin sensitivity was unchanged during the hyperglycaemic clamp. Thus, in response to the two days of basal hyperglycaemia, both the basal and stimulated Beta-cell responses were enhanced and there was no evidence for 'glucose toxicity' to the Beta-cells.
Adult↗
Simple empirical assessment of beta-cell function by a constant infusion of glucose test in normal and type 2 (non-insulin-dependent) diabetic subjects.
The plasma insulin or C-peptide response to a 90-min constant glucose infusion 5 mg.kg ideal body weight-1.min-1 provides Beta-cell assessment comparable to more intensive methods. In 14 diet-treated Type 2 (non-insulin-dependent) diabetic subjects and 12 non-diabetic subjects, plasma insulin and C-peptide concentrations gave near linear plots against simultaneous glucose values. The 'glucose-insulin and glucose-C-peptide vectors' (G-I and G-C vectors), could be extrapolated to predict insulin and C-peptide levels during a 12 mmol/l hyperglycaemic clamp. Predicted concentrations correlated with clamp concentrations, r = 0.94 and r = 0.98 respectively, p less than 0.001, validating the vectors as empirical glucose dose-response curves. The vector slopes correlated highly with %Beta, a mathematical model-derived measure of Beta-cell function using constant infusion of glucose model assessment, Spearman r = 0.95 and 0.93 for insulin and C-peptide, respectively. G-I vector slopes in 21 diet-treated Type 2 diabetic subjects with fasting glucose (mean + 1 SD) 7.5 +/- 2.3 mmol/l, were lower than in 28 non-diabetic subjects, (geometric mean, 1 SD range, 8.4 pmol/mmol (3.3-21.0) and 25.1 pmol/mmol (14.3-44.1), p less than 0.001, respectively), indicating an impaired Beta-cell response. The G-I vector slopes correlated with obesity in both groups (r = 0.54 p less than 0.02 and 0.72, p less than 0.001 respectively), and, in 15 non-diabetic subjects, correlated inversely with insulin sensitivity as measured by a euglycaemic clamp (r = -0.66, p less than 0.01). Thus, Beta-cell function needs to be interpreted in relation to obesity/insulin resistance and, taking obesity into account, only 4 of 21 diabetic patients had Beta-cell function (G-I vector slope) in the non-diabetic range. The fasting plasma glucose in the diabetic subjects correlated inversely with the obesity-corrected G-I and G-C vector slopes (partial r = -0.57, p less than 0.01 and -0.86, p less than 0.001, respectively). The insulin or C-peptide response to the glucose infusion provides a direct empirical measure of the Beta-cell function, which can be interpreted in relation to obesity or to insulin resistance to assess underlying pancreatic responsiveness.
Blood Glucose↗
Understanding "insulin resistance": both glucose resistance and insulin resistance are required to model human diabetes.
A mathematical model of normal glucose/insulin homoeostasis has been based on the known, experimentally determined responses of the liver and periphery to different glucose/insulin concentrations. Different defects of glucose resistance and insulin resistance have been applied to the model to investigate the degree to which these abnormalities could successfully predict the range of fasting glucose and insulin values found in normal, obese, and diabetic subjects. Modeling glucose resistance or insulin resistance at the liver or the periphery alone did not increase the plasma glucose to levels observed in diabetes, even when associated with marked deficiency of beta-cell function. A defect of either glucose resistance or insulin resistance affecting both periphery and liver allowed a wider range of basal glucose and insulin concentration values, but resulted in unphysiologically low hepatic glucose output: with modeling insulin resistance, hyperglycemia suppressed glucose output, whereas with glucose resistance, raised insulin levels suppressed hepatic glucose output. A wide range of glucose and insulin values, with appropriate basal hepatic glucose output, could only be modeled by insulin resistance at both the liver and periphery with additional glucose resistance at the liver. The modeling results are in accord with investigative studies that suggest secondary hepatic and peripheral glucose resistance in response to hyperglycemia. Modeling provides a systematic means of examining the likely effect of different putative defects in a complex physiological system.
Diabetes Mellitus↗
Masking of diabetic phenotype on a low-energy diet despite persistence of impaired insulin response.
Type 2 diabetes has been postulated to be a "thrifty genotype" that aids fuel conservation; to investigate this hypothesis, type 2 diabetic and nondiabetic subjects, normal weight and obese, were studied after both 6 days on a 700-calorie diet and 6 days on a 2,800-calorie diet. On 2,800 calories per day, the median basal plasma glucose was raised in diabetics compared with nondiabetic subjects (median, 5.5 and 4.5 mmol/L, respectively; P = .003), but on the low-energy diet there was no difference (4.1 and 3.7 mmol/L, respectively; P greater than .05). Basal plasma insulin levels were similar in the diabetic and nondiabetic subjects and were twofold to threefold higher on the high- than low-energy diet in both diabetic (median, 7.8 and 3.1 mU/L on high- and low-energy diets, respectively; P = .007) and nondiabetic subjects (6.8 and 2.6 mU/L, respectively; P = .005). Similarly, the postprandial insulin concentrations increased to the same degree on the high- compared with the low-energy diet in diabetic (median postprandial increment, 14.9 and 3.4 mU/L; P = .005) and nondiabetic patients (9.5 and 3.0 mU/L; P = .005) and the beta cells in type 2 diabetes appeared to modulate normally to different calorie intakes. On both diets, the diabetic subjects had an impaired first-phase insulin response to an intravenous glucose load compared with nondiabetic subjects (high-energy diet median first-phase increment, 4.3 and 21.2 mU/L in diabetic and nondiabetic subjects, P = .0007; low-energy diet, 4.0 and 20.4 mU/L, respectively, P = .003).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Recommended roles and responsibilities for chartered engineers, incorporated engineers and engineering technicians.
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Certification↗
Application of structural model of glucose-insulin relations to assess beta-cell function and insulin sensitivity.
A structural mathematical model of glucose-insulin relationships based on known quantitative responses of the major organs involved with glucose metabolism has been computed. Different degrees of beta-cell function and insulin sensitivity can be included, and the effect of their interaction assessed (i) in a steady state, basal homeostasis after an overnight fast and (ii) in response to a glucose infusion. By comparing a patient's basal plasma glucose and insulin (or C-peptide) concentrations with the predictions of a basal homeostatic model, the degree of impairment of beta-cell function and insulin sensitivity can be assessed. Similarly, the plasma glucose and insulin (or C-peptide) concentrations after a continuous glucose infusion can also be compared with predictions from the model to estimate beta-cell function and insulin sensitivity. These assessments of pathophysiology can be applied to data from individual patients or to patient populations.
Blood Glucose↗
Hepatic glucose output in humans measured with labeled glucose to reduce negative errors.
Steele and others have suggested that minimizing changes in glucose specific activity when estimating hepatic glucose output (HGO) during glucose infusions could reduce non-steady-state errors. This approach was assessed in nondiabetic and type II diabetic subjects during constant low dose [27 mumol.kg ideal body wt (IBW)-1.min-1] glucose infusion followed by a 12 mmol/l hyperglycemic clamp. Eight subjects had paired tests with and without labeled infusions. Labeled infusion was used to compare HGO in 11 nondiabetic and 15 diabetic subjects. Whereas unlabeled infusions produced negative values for endogenous glucose output, labeled infusions largely eliminated this error and reduced the dependence of the Steele model on the pool fraction in the paired tests. By use of labeled infusions, 11 nondiabetic subjects suppressed HGO from 10.2 +/- 0.6 (SE) fasting to 0.8 +/- 0.9 mumol.kg IBW-1.min-1 after 90 min of glucose infusion and to -1.9 +/- 0.5 mumol.kg IBW-1.min-1 after 90 min of a 12 mmol/l glucose clamp, but 15 diabetic subjects suppressed only partially from 13.0 +/- 0.9 fasting to 5.7 +/- 1.2 at the end of the glucose infusion and 5.6 +/- 1.0 mumol.kg IBW-1.min-1 in the clamp (P = 0.02, 0.002, and less than 0.001, respectively).
Diabetes Mellitus↗
Suicidality, depression, and substance abuse in adolescence.
The authors assessed the occurrence of suicidal ideation, suicide attempts, major depression, and substance abuse in a sample of 424 apparently healthy college students 16-19 years old. Major depression and substance abuse were independent and interactive risk factors for suicidal ideation and for suicide attempts; substance abuse had a particularly deleterious effect on men. A prolonged desire to be dead was a more specific risk factor for a suicide attempt than was a thought of suicide. The authors conclude that suicidal ideation in the presence of major depression and/or substance abuse in older adolescents should call forth greater concern for lethality.
Adolescent↗
CIGMA as a tool in the study of NIDDM.
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Administration, Oral↗
[Drug risk of hepatic porphyria. Development of an animal experiment model].
Hepatic porphyrias (acute intermittent porphyria, coproporphyria, porphyria variegata and porphyria cutanea) are inherited diseases affecting porphyrin-heme metabolism in the liver. A situation analogous to the latent stage of human hepatic porphyria can be produced in chick embryos by injecting an inhibitor of ferrochelatase (the last enzyme in the heme biosynthesis pathway); the simultaneous injection of a porphyrinogenic drug (e.g. barbiturate) results in a strong increase of liver porphyrin levels, as is found in human hepatic porphyrias. This experimental model facilitates drug screening: drugs that are found to be porphyrinogenic in ovo are potentially dangerous to patients with hepatic porphyria and should be avoided.
Animals↗
Insulin resistance in patients of Asian Indian and European origin with non-insulin dependent diabetes.
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Adult↗
Adolescent depression, alcohol and drug abuse.
The Diagnostic Interview Schedule was employed to ascertain the prevalence of major depressive disorder (MDD), alcohol and substance abuse in a sample of 424 college students aged 16 to 19 years. Applying DSM III criteria, the prevalence of MDD was 6.8 per cent; of alcohol abuse, 8.2 per cent; and of substance abuse 9.4 per cent. Alcohol abuse was associated with MDD, but not with other psychiatric diagnoses. Substance abuse was associated both with MDD and with other psychiatric diagnoses as well. The onset of MDD almost always preceded alcohol or substance abuse suggesting the possibility of self-medication as a factor in the development of alcohol or substance abuse.
Adolescent↗
Asian diabetes in Britain: a clinical profile.
The clinical features of large unselected groups of Asian (401) and European (491) patients attending a diabetic clinic were compared. The prevalences of symptomatic ischaemic heart disease, hypertension, retinopathy, and lens opacities were similar in the two groups, despite the shorter known duration and the relative youth of the Asian patients. Pedal pulses were more often absent in Europeans, whereas in the age-group 20-64 years, ankle and knee reflexes were more often unobtainable in Asians. The degree of adiposity was similar in the two groups, but was less in Asian males than females. A first-degree diabetic relative was reported more commonly in Asians than in Europeans. These findings are important in relation to the exceptionally high prevalence of diabetes recently described in the Southall Asian community.
Adult↗