Role of glucose and insulin resistance in development of type 2 diabetes mellitus.
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Diabetes Mellitus, Type 2↗
Biomedical subjects
V Wynn
Publications and source records attributed to V Wynn.
Insulin resistance and cigarette smoking.
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Cholesterol↗
Cholesterol, apolipoproteins, and the risk of myocardial infarction.
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Cholesterol, HDL↗
Effect of simvastatin on high density lipoprotein subfractions and apolipoproteins in type IIa hypercholesterolemia.
Changes in plasma concentrations of high density lipoproteins (HDL) and triglycerides may partly explain the ability of cholesterol-lowering drugs to decrease the incidence of coronary heart disease. We measured the response of fasting plasma lipids, lipoproteins, and apolipoproteins in 46 subjects with Type IIa hypercholesterolemia treated with simvastatin for 3 months. The initial dose of simvastatin (10 mg/day) was subsequently increased up to 40 mg/day if the plasma cholesterol concentration had not fallen below 5.2 mmol/l. Plasma concentrations of HDL cholesterol and of the apolipoproteins AI and AII were increased by simvastatin. The increase in HDL cholesterol (9%) was due to increases in both subfractions (HDL2 17%; HDL3 7%), changes that would be consistent with a beneficial effect on cardiovascular risk. Simvastatin decreased plasma triglyceride concentrations by 25%. Plasma total cholesterol concentrations fell by 35% after 3 months of treatment; this fall was proportional to the initial concentration and was due almost entirely to a 45% fall in low density lipoprotein cholesterol. In contrast, plasma concentrations of lipoprotein Lp(a) were not affected by simvastatin.
Anticholesteremic Agents↗
Insulin resistance--modelling studies.
Elevated insulin concentrations are independent predictors of coronary heart disease (CHD) and are related to high blood pressure, low serum HDL-cholesterol and elevated serum triglyceride. Insulin resistance is a major determinant of the plasma insulin concentration. Computer modelling of plasma glucose, insulin and C-peptide concentrations during an intravenous glucose tolerance test enables quantification of the determinants of plasma insulin concentration. The association between risk markers of CHD and model-derived measures of determinants of plasma insulin concentration in a group of healthy males has been investigated. In univariate linear regression analysis of the glucose, insulin and C-peptide data, the incremental insulin area during the second phase (10-180 min.) was found to be the strongest predictor of lipid, lipoprotein and blood pressure variables. Variations in insulin sensitivity and hepatic insulin throughput contribute to variation in the insulin response and may be secondary correlates of lipids, lipoproteins and blood pressure.
Adult↗
Comparison of transdermal and oral estrogen-progestin replacement therapy: effects on serum lipids and lipoproteins.
OBJECTIVE: We attempted to ascertain whether transdermal postmenopausal estrogen-progestin therapy has the typical effects of oral therapy on serum lipoprotein risk markers for cardiovascular disease. STUDY DESIGN: Sixty-one postmenopausal women were randomized to receive either transdermal continuous 17 beta-estradiol, 0.05 mg/day, with transdermal cyclic norethindrone acetate, 0.25 mg/day, or oral continuous conjugated equine estrogens, 0.625 mg/day, with oral cyclic dl-norgestrel, 0.15 mg/day. Twenty-nine untreated subjects served as controls. Lipoprotein profiles at 3 and 6 months were compared with baseline values by means of analysis of variance. RESULTS: In the estrogen-alone phase both therapies reduced serum levels of total and low-density lipoprotein cholesterol; high-density lipoproteins were largely unchanged. Oral therapy increased triglycerides whereas this lipid fell with transdermal therapy. In the combined phase of the cycle both therapies reduced triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. CONCLUSION: Transdermal and oral therapies had similar effects on lipoprotein cholesterol but different effects on triglycerides.
Administration, Cutaneous↗
Clinical and metabolic considerations of long-term oral contraceptive use.
Newer lower dose formulations are associated with an improved cardiovascular disease risk marker profile, which supports their use for longer periods and among older women. Epidemiologic studies of the newer formulations are limited. Without clinical information, an evaluation of the effects of more recent formulations on metabolic risk markers for cardiovascular disease is useful. In a large cross-sectional study, a reduction in the progestin dose and use of alternative progestins substantially reduced the proportion of oral contraceptive users with values associated with an increased risk of cardiovascular disease. No progression in metabolic changes was found by analyzing the effect of the duration of oral contraceptive use. The user's age interacted positively with the oral contraceptive--induced increase in serum triglyceride levels, but there was no interaction of age with the oral contraceptive's effect on oral glucose tolerance, glucose and insulin responses, low-density lipoprotein cholesterol, or high-density lipoprotein subfraction 2 cholesterol levels.
Age Factors↗
An apparently anomalous relationship between insulin and C-peptide concentrations in their initial response to intravenous glucose.
Intravenous glucose tolerance tests (IVGTTs) with determination of plasma glucose, insulin, and C-peptide concentrations were performed in 136 men and 154 women. It was found that in 4% of men and 12% of women the plasma concentration of insulin exceeded that of C-peptide during the initial response to glucose. Subjects exhibiting this phenomenon had lower fasting and post-glucose C-peptide concentrations than those who did not; however, there were no statistically significant differences in glucose or insulin concentrations. The phenomenon was age-related, being absent from individuals aged 35 years and under, while in older age groups it appeared to be more prevalent in women than in men, suggesting an additional effect of menopause. However, in three follow-up IVGTTs performed in a subgroup of postmenopausal women over a period of 18 months, the phenomenon failed to recur in any of the individuals who first exhibited it, although it did occur in others. Our observations suggest the existence of an age-related but intermittent decrease in pancreatic insulin secretion, which does not lead to any significant change in plasma insulin concentrations, possibly as a result of reduced hepatic uptake of insulin. One consequence appears to be an excess of insulin over C-peptide during the early part of the IVGTT, which is probably related to the different distributional kinetics of the two peptides.
Adult↗
Danazol induces resistance to both insulin and glucagon in young women.
1. Danazol elevates plasma insulin, plasma glucagon and serum low-density lipoprotein concentrations and reduces the serum high-density lipoprotein concentration. 2. Associations between these disturbances were studied in 17 women receiving danazol therapy for endometriosis. Eleven women underwent intravenous glucose tolerance tests with measurement of plasma glucose, insulin, C-peptide and glucagon concentrations and modelling analysis of intravenous glucose tolerance test concentration profiles. Six women underwent glucagon sensitivity tests. Serum concentrations of lipids and lipoproteins were measured in all cases. 3. Danazol reduced the fasting plasma glucose and insulin concentrations, but markedly raised the fasting plasma glucagon concentration. The insulin and C-peptide responses to the intravenous glucose tolerance test were increased twofold and the net decrement in glucagon concentration was increased tenfold. The glucose response to the intravenous glucose tolerance test was unaffected. Insulin sensitivity was reduced by 55%. Both first-phase plasma insulin responsiveness and net first-phase pancreatic insulin secretion were increased; insulin half-life was prolonged. The glucose response to the glucagon sensitivity test was reduced on treatment. The calculated low-density lipoprotein cholesterol level rose by 20%, whereas high-density lipoprotein cholesterol level fell by 47%. None of these changes in serum lipoprotein levels correlated with changes in insulin metabolism. In general, metabolic changes normalized after 3 months. 4. Danazol increases the sensitivity of pancreatic insulin and glucagon secretion to glucose. Danazol-induced insulin and glucagon resistance could be due to receptor down-regulation resulting from hypersecretion of insulin and glucagon.
Adult↗
Evaluation of four mathematical models of glucose and insulin dynamics with analysis of effects of age and obesity.
Despite there being a number of mathematical models of glucose and insulin dynamics, there have been no evaluations of their operation in large groups of subjects. We have carried out intravenous glucose tolerance tests on a group of 182 healthy males, with determination of plasma glucose, insulin, and C-peptide concentrations. Parameters of glucose and insulin dynamics were determined using the minimal model of glucose disappearance, a minimal model of peripheral insulin delivery, and two different models of pancreatic insulin secretion (models I and II). Successful identifications were obtained in 96, 95, 76, and 100% of cases, respectively. The models were evaluated in terms of their ability to recover effects of obesity and aging on carbohydrate metabolism. The glucose disappearance model successfully detected the insulin resistance of both obesity and aging, whereas the peripheral insulin delivery model indicated an increased responsiveness of insulin delivery to glucose in obesity but detected no significant change associated with age. No parameter of pancreatic secretion model I exhibited a significant association with either age or obesity. Insulin secretion model II indicated that the hyperinsulinemia accompanying obesity resulted from both increased pancreatic secretion and decreased hepatic insulin uptake.
Adult↗
Influence of insulin resistance, secretion, and clearance on serum cholesterol, triglycerides, lipoprotein cholesterol, and blood pressure in healthy men.
Relations between serum lipids, lipoproteins, blood pressure, and insulin metabolism were investigated in 158 healthy men aged 19-77 years and with body mass indexes (BMIs) of 19-41 kg.m-2. Mathematical modeling analysis of glucose, insulin, and C-peptide concentrations during an intravenous glucose tolerance test was used to measure parameters of insulin metabolism. In univariate analysis, both fasting and postglucose insulin concentrations showed significant positive associations with fasting serum triglyceride levels (r = 0.33 and 0.38, respectively) and systolic (r = 0.22 and 0.26) and diastolic (r = 0.21 and 0.24) blood pressure and negative associations with high density lipoprotein subfraction 2 cholesterol (HDL2; r = -0.21 and -0.25). In multivariate analysis, the associations between insulin and HDL2 cholesterol concentrations were found to depend on triglyceride levels. Insulin resistance and basal pancreatic insulin secretion showed significant positive associations with serum triglycerides, which were independent of the effects of age, BMI, and fat distribution. Hepatic insulin throughout was independently associated with HDL2 cholesterol. Associations of insulin-related variables with blood pressure were generally dependent on age and BMI. These results underline the importance of insulin sensitivity and insulin concentrations as determinants of triglyceride metabolism. They also indicate a close relation between hepatic insulin handling and HDL2 concentration that is independent of triglyceride metabolism.
Adult↗
Insulin resistance, secretion, and metabolism in users of oral contraceptives.
Studies of insulin employing the oral glucose tolerance test demonstrate marked differences between the effects of different oral contraceptives, but provide little insight into the underlying disturbances. We investigated the metabolic basis of these disturbances by computer modelling of iv glucose tolerance test glucose, insulin, and C-peptide concentration profiles. Insulin resistance, secretion, and metabolism were evaluated in 296 oral contraceptive users and 95 nonusers. Four estrogen/progestin combinations, with similar estrogen but differing progestin contents, and 1 progestin-only formulation were studied. Effects on iv glucose tolerance test glucose, insulin, and C-peptide concentrations varied according to progestin content, with levonorgestrel-containing combinations having the greatest effect, followed by desogestrel and norethindrone. However, these formulations increased insulin resistance to a similar extent. The progestin-only formulation did not affect insulin resistance. Levonorgestrel combinations increased second phase pancreatic insulin secretion by 60-90%, but did not affect the insulin half-life. The desogestrel combination increased the insulin half-life by 28%, but did not affect insulin secretion. The effects of different combined oral contraceptives on glucose tolerance test glucose, insulin, and C-peptide concentration profiles appears to be due to a combination of estrogen-induced insulin resistance and progestin-associated changes in insulin half-life.
Adolescent↗
Effect of body mass index and fat distribution on insulin sensitivity, secretion, and clearance in nonobese healthy men.
The effects of variation in body mass index (BMI; kg/m2) and body fat topography on insulin sensitivity, secretion, and clearance were determined in a group of 146 nonobese nondiabetic males. Volunteers underwent an i.v. glucose tolerance test, with determination of plasma glucose, insulin, and C-peptide levels. BMI was taken as a measure of overall adiposity, while skinfold thickness ratios were used to assess the centrality of fat distribution and the localization of central fat within the trunk. Measurements of insulin sensitivity, secretion, and clearance were obtained by mathematical modelling of the i.v. glucose tolerance test concentration profiles. Increasing BMI and centrality of fat distribution had no significant effect on glucose tolerance, but were independently associated with diminished insulin sensitivity and increased insulin secretion. The elevation in secretion occurred almost entirely during the second phase of pancreatic insulin release. These results show that the variations in insulin sensitivity and secretion that have often been reported in obesity are also present in a group within the normal range of BMI. However, the absence of any decrease in hepatic uptake, also reported in the obese, indicates that this might be an additional mechanism recruited to maintain glycemic control at higher levels of adiposity. Localization of central fat in the lower trunk was correlated with elevated first phase insulin secretion, but no concomitant change in insulin sensitivity. There may, therefore, be a direct effect of the distribution of central fat on insulin secretion.
Adipose Tissue↗
Inverse relationship between serum Lp(a) levels and first-phase insulin secretion.
Relationships between serum Lp(a) levels and insulin metabolism were investigated in 147 healthy nonobese men attending an executive health-screening program. Each subject received an IVGTT with measurement of plasma levels of glucose, insulin, and C-peptide. An inverse relationship was seen with the first-phase plasma insulin response when subjects were stratified into quartile ranges of the serum Lp(a) distribution. This relationship was supported by mathematical modeling analyses of these data, which revealed an inverse relationship between serum Lp(a) levels and first-phase pancreatic insulin secretion and plasma insulin responsiveness to glucose.
Blood Glucose↗
Relationships among critical thinking skills, academic achievement, and misconceptions about psychology.
Two groups of 60 students each were selected from introductory college psychology classes. One consisted of high academic achievers, the other of average achievers. They were given the McCutcheon Test of Misconceptions, a 65-item, multiple-choice test designed to measure common misconceptions about psychology. Subsequently, they were also given the Watson-Glaser Critical Thinking Appraisal. Both groups made many errors on the McCutcheon test, but high academic achievers made significantly fewer errors on both the McCutcheon test and the Watson-Glaser than average achievers. A stepwise multiple regression consisting of Watson-Glaser subscales 1 (the ability to draw valid inferences) and 4 (ability to weigh and interpret evidence) and GPA successfully predicted McCutcheon test scores (R = .43). This suggests that even beginning students with high grades and good critical thinking skills are likely to harbor many misconceptions about psychology.
Achievement↗
Case studies in working memory: a case for single cases?
Patterns of cognitive deficit in single neuropsychological cases are common sources of evidence for theories of normal cognition. In particular, the working memory model has benefited from data obtained from a number of contrasting patients, in some cases resulting in modifications of the working memory model. In this paper, patterns of data from short-term memory patients and anarthric patients are compared with patterns of data from normal subjects. The patterns of patient data that were unlike those patterns typically found for groups of normal subjects, could be incorporated within a modified version of the articulatory loop component of the working memory model. However a small number of individual normal subjects also did not show the pattern that is reported on the basis of average performance of groups of normal subjects. This causes some difficulty in interpreting those data from such 'aberrant normal' patterns, and those data from single patients with functional cognitive deficits. The implications of these findings for the interpretation of neuropsychological data are discussed in the context of the working memory model, but with the intention of making a general point pertaining to the development of functional models of cognition. It is argued that single case studies should continue to provide a useful source of evidence, providing that care is exercised in considering the implications of such data for models of normal cognition.
Adult↗
Lipid and carbohydrate metabolism in premenopausal women given subdermal estradiol implants.
Fifteen premenopausal women were studied before and 6 weeks after receiving subcutaneous implants of 100 mg estradiol. Serum estradiol levels doubled; increases were also seen in fasting serum total cholesterol and in high-density lipoprotein cholesterol (HDL). This increase was confined to the HDL2 subfraction, and was not reflected in the HDL apolipoproteins. Low density lipoprotein (LDL) cholesterol levels were unchanged, as were those of apolipoprotein B, the major protein component of LDL. Carbohydrate metabolism was assessed in a subgroup of 12 women. Estrogen implantation reduced fasting plasma glucose levels but did not alter the plasma glucose response to an oral glucose tolerance test. Plasma insulin levels were unchanged both in the fasted state and during the glucose tolerance test. Our findings indicate that parenteral administration of estradiol can alter lipid and carbohydrate metabolism in premenopausal women.
Adult↗
Oral contraceptives and metabolic risk markers for coronary heart disease.
Disturbances in both the plasma lipid profile and in insulin handling have been implicated in the development of coronary heart disease (CHD). Estrogens and progestins are known to affect significantly both lipid and insulin metabolism. Since an increased incidence of myocardial infarction has been identified among users of oral contraceptives (OCs), the metabolic effect of these drugs on risk factors for CHD is of interest. Comparison of a range of monophasic and triphasic OCs that differ primarily in their progestin content has shown that lowering the progestin dose and using a less androgenic steroid reduce the impact on both low-density lipoproteins and high-density lipoproteins (HDLs). In terms of the HDL-2 subfraction, a lipoprotein class that may be of special relevance to the development of CHD, low-dose norethindrone and desogestrel monophasic agents had the least adverse effect. Triglyceride levels were increased by the low-dose OCs used in this study; this may be an unavoidable consequence of current trends in OC development. However, the clinical significance of these increased triglyceride levels is not clear. Glucose tolerance deteriorated similarly with all the formulations in this study, although the effect on insulin concentrations was less marked with formulations containing lower doses of progestins. It was concluded that reducing the progestin dose and changing the progestin type effectively reduce the adverse impact of OCs on metabolic risk for CHD. Although further study is recommended, the use of OC formulations without adverse effects on risk profile is indicated.
Adolescent↗