Biomedical subjects

F Abbasi

Publications and source records attributed to F Abbasi.

At least 37 records · Page 2Linked to original sources

PubMed2000

The relationship between glucose disposal in response to physiological hyperinsulinemia and basal glucose and free fatty acid concentrations in healthy volunteers.

This study was initiated to see if defects in the ability of physiological hyperinsulinemia (approximately 60 microU/mL) to stimulate glucose uptake in healthy, nondiabetic volunteers are associated with increases in concentrations of plasma glucose and free fatty acid (FFA) when measured at basal insulin concentrations (approximately 10 microU/mL). We recruited 22 volunteers (12 women and 10 men) for these studies, with a (mean +/- SEM) body mass index of 24.8 +/- 0.5 kg/m2. Resistance to insulin-mediated glucose disposal during physiological hyperinsulinemia was determined by suppressing endogenous insulin and determining the steady-state plasma glucose (SSPG) and steady-state plasma insulin (SSPI) concentrations at the end of a 3-h infusion, period during which glucose (267 mg/m2 x min) and insulin (32 mU/m2 x min) were infused at a constant rate. Glucose, insulin and FFA concentrations were also measured in response to infusion rates of glucose (50 mg/m2 x min) and insulin (6 mU/m2 x min). The SSPI concentration (mean +/- SEM) during physiological hyperinsulinemia was 64 +/- 3 microU/mL), in contrast to 12 +/- 0.4 microU/mL during the basal insulin study. The results demonstrated a significant relationship between SSPG concentration in response to physiological hyperinsulinemia (SSPG60) and SSPG(Basal) (r = 0.57, P < 0.01) and FFA(Basal) (r = 0.73, P < 0.001). Furthermore, FFA(Basal) and SSPG(Basal) were significantly correlated (r = 0.47, P < 0.05). Comparison of the seven most insulin-resistant and seven most insulin sensitive individuals (SSPG60 values of 209 +/- 16 vs. 64 +/- 8 mg/dL) revealed that the insulin-resistant group also had significantly higher SSPG(Basal) (105 +/- 5 vs. 78 +/- 7 mg/dL, P < 0.01) and FFA(Basal) (394 +/- 91 vs. 104 +/- 41, P < 0.02) concentrations. However, random fasting plasma glucose and FFA concentrations of the two groups were not different. The results presented demonstrate that individual differences in the ability of elevated insulin concentrations to stimulate muscle glucose disposal are significantly correlated with variations in insulin regulation of plasma glucose and FFA concentrations at basal insulin concentrations.

Adult↗

PubMed2000

Carbohydrate-induced hypertriglyceridemia: an insight into the link between plasma insulin and triglyceride concentrations.

This study was initiated to test the hypothesis that endogenous hypertriglyceridemia results from a defect in the ability of insulin to inhibit the release of very low-density lipoprotein-triglyceride (TG) from the liver. To accomplish this goal, plasma glucose, insulin, free fatty acid (FFA), and TG concentrations were compared in 12 healthy volunteers, in response to diets containing either 40% or 60% of total calories as carbohydrate (CHO). The protein content of the two diets was similar (15% of calories), and the fat content varied inversely with the amount of CHO (45% or 25%). The diets were consumed in random order, and measurements were made of plasma glucose, insulin, FFA, and TG concentrations at the end of each dietary period, fasting, and at hourly intervals following breakfast and lunch. The results indicated that the 60% CHO diet resulted in higher fasting plasma TG concentrations associated with higher day-long plasma insulin and TG concentrations, and lower FFA concentrations. These results do not support the view that hypertriglyceridemia is secondary to a failure of insulin to inhibit hepatic TG secretion.

Blood Glucose↗

PubMed2000

Relationship between several surrogate estimates of insulin resistance and quantification of insulin-mediated glucose disposal in 490 healthy nondiabetic volunteers.

OBJECTIVE: The goal of this study was to define the relationship between a quantitative measure of the ability of physiological hyperinsulinemia to stimulate glucose disposal and several surrogate measures of insulin resistance. RESEARCH DESIGN AND METHODS: Insulin-mediated glucose disposal was quantified in 490 healthy nondiabetic volunteers by determining the steady-state plasma glucose (SSPG) concentration in response to a continuous infusion of somatostatin, insulin, and glucose. Because the steady-state plasma insulin concentration was similar in all subjects during the infusion (approximately 60 microU/ml), the SSPG concentration provided a direct estimate of insulin-mediated glucose disposal. Relationships between this specific measure of insulin resistance and several surrogate estimates of insulin resistance based on plasma glucose and insulin concentrations were then defined. RESULTS: The surrogate measure of insulin resistance most closely related to the direct determination of insulin action was the total integrated insulin response to a 75-g oral glucose challenge with correlation coefficients (r) varying from 0.67 to 0.79. Fasting plasma insulin concentration was significantly correlated (r = 0.61, P<0.001) to the specific estimate of insulin action. Two other surrogate estimates of insulin action, the ratio of fasting glucose-to-fasting insulin concentration and the homeostasis model assessment for insulin resistance, were no more closely related to SSPG than the fasting plasma insulin concentration. CONCLUSIONS: The total integrated insulin response to oral glucose is the best surrogate measure of insulin resistance, accounting for approximately two-thirds of the variability in insulin-mediated glucose disposal. Fasting insulin concentration accounted for approximately one-third of the variability in insulin-mediated glucose disposal, and the use of fasting plasma glucose and insulin concentrations to calculate more sophisticated estimates of insulin resistance appears to offer little advantage over the fasting plasma insulin concentration. Given the large number of nondiabetic individuals in this study, the results should have general application in population-based studies, providing evidence for both the utility and limitation of the use of these surrogate measures.

Adult↗

PubMed1999

Mononuclear cell adherence to cultured endothelium is enhanced by hypertension and insulin resistance in healthy nondiabetic volunteers.

BACKGROUND: This study was initiated to compare the adherence to cultured endothelial cells of mononuclear cells isolated from normotensive and hypertensive individuals. METHODS AND RESULTS: Mononuclear cell binding to endothelium was greater in patients with hypertension (32+/-1 versus 25+/-2; P<0.001) than in normal volunteers. There was a significant relationship (r=0.42, P<0. 01) between mononuclear cell binding and mean arterial pressure, independent of differences in age, sex, and body mass index. A significant relationship also existed between insulin resistance (estimated by the steady-state plasma glucose concentration during the insulin suppression test) and mononuclear cell binding in both the normotensive (r=0.86, P<0.001) and hypertensive (r=0.74, P<0. 001) groups. Furthermore, multiple regression analysis demonstrated an independent relationship (P<0.001) between mononuclear cell binding and both steady-state plasma glucose and hypertensive status. CONCLUSIONS: These results indicate that both hypertension and insulin resistance lead to changes in mononuclear cells that increase their adherence to cultured endothelial cells.

Cell Adhesion↗

PubMed1999

Plasma homocysteine concentrations in healthy volunteers are not related to differences in insulin-mediated glucose disposal.

This study was initiated to test the hypothesis that plasma homocysteine concentrations are increased in insulin resistant individuals. For this purpose, the relationship between insulin resistance, as assessed by the steady-state plasma glucose (SSPG) concentration during the insulin suppression test, and fasting plasma homocysteine concentration was defined in 55 healthy volunteers. The results indicated that homocysteine concentrations did not vary as a function of SSPG concentrations (r = 0.02, P = 0.88). Furthermore, mean (+/- S.E.M.) plasma homocysteine concentrations were similar (8.2+/-0.4 vs. 8.7+/-0.7 micromol/l) in individuals classified as being either insulin sensitive (SSPG <100 mg/dl) or insulin resistant (SSPG >180 mg/dl). On the other hand, SSPG concentration was significantly correlated with fasting plasma insulin (r = 0.58, P<0.001), triglycerides (r = 0.34, P<0.05), and HDL-cholesterol (r = -0.36, P = 0.04) concentrations. These data strongly suggest that the increased risk of atherosclerosis associated with increased plasma homocysteine concentrations is unrelated to insulin resistance and/or the metabolic abnormalities associated with it.

Adult↗

PubMed1999

Effects of menopause on seizures in women with epilepsy.

PURPOSE: Although important associations between epilepsy and women's hormonal phases are described, the relation of menopause to epilepsy has received little attention. METHODS: By using a structured interview, we studied menopausal women with epilepsy seen at the University of Maryland Epilepsy Center over a 1-year period from 1994 to 1995. We analyzed the characteristics and temporal relation of the seizures to menopause and compared the frequency and severity of the seizures with those in a similar group of premenopausal women. RESULTS: We identified 61 menopausal women (46 who were postmenopausal and 15 perimenopausal) and compared them with 46 premenopausal women. No statistically significant differences were noted in either the frequency or the severity of seizures comparing all menopausal or only postmenopausal with premenopausal women. However, 12 (20%) of the 61 menopausal women noted that their seizures first began during or after menopause, with eight having no proven cause for their seizures. Many individual women described changes in their seizures with menopause. Among the 61 menopausal women, 49 had established epilepsy before the onset of menopause, and 20 (41%) reported worsening of their seizures with menopause, 13 (27%) noted improvement, and 16 (33%) described no changes. These observations were similar for peri- and postmenopausal women. Of the 15 menopausal women taking hormone replacement therapy, the six taking progestin were significantly less likely to report worsening of their seizures. CONCLUSIONS: These findings support the view that hormonal influences are important in women with seizures. Although, in aggregate, menopausal (combined perimenopausal and postmenopausal) and postmenopausal women's seizures were similar in frequency and severity to those of other women, menopause was associated with changes in seizures for some women. Moreover, menopause may be a previously unrecognized factor for some new-onset seizures. The relations between menopause and epilepsy deserve to be more fully investigated.

Adult↗

PubMed1999

Comparison of plasminogen activator inhibitor-1 concentration in insulin-resistant versus insulin-sensitive healthy women.

The primary goal of this investigation was to see whether plasminogen activator inhibitor-1 (PAI-1) concentrations varied as a function of differences in insulin-mediated glucose disposal in 2 groups of healthy women matched for every other variable that might play a role in regulation of PAI-1. For this purpose, we recruited 32 healthy women, divided on the basis of their steady-state plasma glucose (SSPG) concentrations during the insulin suppression test into an insulin-resistant (SSPG=216+/-12 mg/dL, n=16) and an insulin-sensitive (94+/-6 mg/dL, n=16) group. PAI-1 antigen concentrations were significantly higher (26+/-4 versus 14+/-3 ng/mL, P<0.02) in the insulin-resistant group. In addition, fasting plasma insulin (18+/-3 versus 11+/-2 microU/mL, P<0.02) and triglyceride (160+/-19 versus 93+/-10 mg/dL, P<0.001) concentrations were higher in the insulin-resistant individuals, whereas HDL concentrations were lower (44+/-3 versus 58+/-3 mg/dL, P<0.005). However, the 2 groups were essentially identical in terms of age, menopausal status, hormone replacement therapy, body mass index (BMI), ratio of waist-to-hip girth, and blood pressure. When the experimental population was considered as 1 group, there were statistically significant correlations between PAI-1 antigen and the following variables: adjusting for differences in age and BMI, SSPG (r=0.56, P<0.001); triglyceride (r=0.39, P<0.05); and HDL cholesterol (r=-0. 65, P<0.001) concentrations. Finally, multiple regression analysis revealed the major determinants of PAI-1 to be insulin resistance, or insulin concentration, and HDL cholesterol. These results: 1) demonstrate that PAI-1 concentrations are higher in healthy, insulin-resistant women as compared with insulin-sensitive individuals, independent of differences in BMI or ratio of waist-to-hip girth; and 2) provide another mechanism by which insulin-resistant individuals are at increased thrombotic cardiovascular risk.

Age Factors↗

PubMed1999

Fasting remnant lipoprotein cholesterol and triglyceride concentrations are elevated in nondiabetic, insulin-resistant, female volunteers.

This study was initiated to test the hypothesis that plasma concentrations of remnant lipoproteins would be higher after an overnight fast in insulin-resistant compared to insulin-sensitive volunteers. Forty-three healthy nonobese women were studied, divided into insulin-resistant (n = 21) and insulin-sensitive (n = 22) groups on the basis of their steady state plasma glucose (SSPG) concentration at the end of a 180-min infusion of octreotide acetate, insulin, and glucose. Under these conditions, steady state plasma insulin concentrations are similar in all subjects (approximately 60 microU/mL), and the higher the SSPG concentrations, the more insulin resistant the individual. By selection, mean (+/-SEM) SSPG concentrations were significantly higher (P < 0.001) in the insulin-resistant group (210 +/- 7 vs. 78 +/- 3 mg/dL). In addition, the insulin-resistant group had higher triglycerides (198 +/- 27 vs. 101 +/- 12 mg/dL; P < 0.005) and lower high density lipoprotein cholesterol (48 +/- 4 vs. 60 +/- 4 mg/dL; P < 0.05) concentrations. Finally, insulin resistance was associated with higher remnant lipoprotein particle concentrations of cholesterol (7.2 +/- 0.8 vs. 4.4 +/- 0.3; P < 0.005) and triglycerides (22.2 +/- 3.4 vs. 8.5 +/- 1.0; P < 0.001). All of these differences were seen despite the fact that the two groups were similar in terms of age and body mass index. These results identify additional abnormalities in lipoprotein metabolism that may contribute to the increased risk of coronary heart disease seen in insulin-resistant, nondiabetic subjects (syndrome X).

Blood Glucose↗

PubMed1999

Differences in insulin resistance do not predict weight loss in response to hypocaloric diets in healthy obese women.

The current study was initiated to determine whether insulin resistance and/or hyperinsulinemia affected the ability of obese individuals to lose weight in response to hypocaloric diets. Thirty-one obese, nondiabetic women, with values for body mass index ranging from 28.0-35.0 kg/m2, volunteered for this program. Resistance to insulin-mediated glucose disposal was assessed by determining their steady state plasma insulin and glucose concentration during the last 30 min of a 180-min infusion of somatostatin, insulin, and glucose. The total integrated insulin response to breakfast and lunch was also determined. After the baseline measurements, volunteers were placed on a hypocaloric diet calculated to lead to a minimum weekly loss of 1% of ideal body weight. Individuals who met the criteria after 30 days of dieting were defined as weight loss successes (n = 20) and continued on the diet for another 30 days. Individuals not meeting the criteria were designated as weight loss failures (n = 12) and were discharged from the study. There was a mean (+/-SEM) weight loss at 60 days of 9.2 +/- 0.4 kg in the 20 individuals defined as weight loss successes, but there was no correlation between weight loss and either steady state plasma glucose or the total integrated insulin response (r < 0.1; P > 0.83). Furthermore, using the same criteria to define insulin sensitivity and insulin resistance as those for therapeutic successes, the therapeutic failures comprised six insulin-sensitive and five insulin-resistant subjects. In summary, insulin-mediated glucose disposal varied widely in nondiabetic, obese women, and there was no relationship between baseline insulin resistance or total integrated insulin response and weight loss. It is concluded that the ability to lose weight on a calorie-restricted diet over a short time period does not vary in obese, healthy women as a function of insulin resistance or hyperinsulinemia.

Adult↗

PubMed1999

Can changes in plasma insulin concentration explain the variability in leptin response to weight loss in obese women with normal glucose tolerance?

The aim of this study was to test the hypothesis that the fall in circulating insulin concentration associated with moderate weight loss determines the associated decrease in plasma leptin concentration. For this purpose, 12 healthy, nondiabetic, obese women were studied before and after an average weight loss of 9.5 kg (11.2% of initial body weight). Plasma leptin concentrations fell from a mean (+/-SE) value of 35 +/- 3 to 17 +/- 2 ng/mL (P < 0.001) in association with the loss of weight. However, there was no correlation between the decline in leptin concentration and the associated fall in weight, body mass index, fat mass, or percent body fat. Furthermore, no correlation was seen among changes in fasting plasma glucose or insulin concentrations, the 8-h integrated plasma glucose response to breakfast and lunch, or the estimate of insulin-mediated glucose disposal. The only measured variable that correlated with the fall in plasma leptin concentration (r = 0.78; P < 0.005) was the decline in the 8-h integrated plasma insulin response after weight loss (from 304 +/- 44 to 232 +/- 36 microU/8 h x mL; P < 0.001). Finally, multivariate regression analysis, using various estimates of degree of obesity, insulin resistance, integrated glucose response, and integrated insulin response as dependent variables, indicated that only the insulin response was independently related to the decrease in leptin concentration (P = 0.035). The fall in integrated insulin response accounted for 66% of the variance in leptin concentrations after weight loss, and this was true no matter what the estimate of change in degree of obesity. In addition to offering an explanation for the variance in postweight loss leptin concentrations, these data provide further evidence of the importance of ambient insulin concentrations in the regulation of plasma leptin concentrations.

Adult↗

PubMed1998

Relationship between insulin resistance and partially oxidized LDL particles in healthy, nondiabetic volunteers.

This study was performed in 36 healthy volunteers to define the relationship between plasma concentrations of partially oxidized low density lipoprotein (poxLDL), plasma glucose and insulin responses to oral glucose, and steady-state plasma glucose (SSPG) concentrations after a 180-minute infusion of somatostatin, insulin, and glucose. The concentration of poxLDL was estimated by determining the amount of conjugated dienes formed during in vitro LDL oxidation in the presence or absence of alanine. Under these conditions, the greater the in vitro antioxidant effect of alanine, the lower the amount of poxLDL that was present in plasma. The results demonstrated that plasma poxLDL concentration was significantly correlated with plasma glucose (r=.53, P<.001) and insulin (r=.43, P<.01) responses, SSPG concentrations (r=.53, P<.001), and plasma triglyceride (r=.42, P<.01) and HDL cholesterol (r=-.50, P<.002) concentrations. Furthermore, these relationships persisted when the data were corrected for differences in age, sex, body mass index, and the ratio of waist to hip girth. Of note, there was no correlation between poxLDL and LDL cholesterol concentration. When SSPG was entered along with age, sex, body mass index, and waist-to-hip ratio in a multiple regression model, SSPG alone was a significant prediction of poxLDL (r-=.37, P<.02). The addition of plasma glucose and insulin responses and triglyceride and HDL cholesterol concentrations increased the r2 to only .47. These results show that the amount of poxLDL in plasma is significantly correlated with insulin resistance (ie, SSPG) and its metabolic consequences.

Adult↗

PubMed1998

Plasma leptin concentrations do not appear to decrease insulin-mediated glucose disposal or glucose-stimulated insulin secretion in women with normal glucose tolerance.

The aim of this study was to test the hypothesis that plasma leptin concentrations contributed to the pathophysiology of NIDDM by decreasing both insulin-mediated glucose disposal and glucose-stimulated insulin secretion. The study was performed in 60 women with normal oral glucose tolerance. Differences in insulin-mediated glucose disposal were determined by comparing the steady-state plasma glucose (SSPG) concentrations attained at the end of a 180-min constant infusion of somatostatin, glucose, and insulin, while comparisons of glucose-stimulated insulin secretion were based on the incremental increase in insulin concentration 30 min after an oral glucose challenge (deltaIns) as compared with the fasting value. The results showed that the higher the fasting plasma leptin concentration, the greater the degree of insulin resistance (r = 0.47, P < 0.01). Furthermore, multiple regression analysis indicated that the relationship between leptin and SSPG was independent of age and degree of obesity as estimated by BMI. However, since the total integrated plasma insulin response was highly correlated with both SSPG (r = 0.80, P < 0.001) and leptin (r = 0.55, P < 0.01), multiple regression analysis was repeated, adding total insulin response to the model. When this was done, the significant relationship between leptin and SSPG disappeared, whereas both BMI (P < 0.03) and insulin response (P < 0.001) were correlated with SSPG. A significant relationship between leptin and deltaIns was seen, but it was a positive one (r = 0.31, P < 0.02), not a negative one as would be expected if circulating levels of leptin inhibited glucose-stimulated insulin secretion. Furthermore, multiple regression analysis could only confirm an independent relationship between deltaIns and SSPG, but not between deltaIns and leptin. The results of these studies do not support the view that circulating leptin has a primary effect on either insulin action or secretion in normal female volunteers. It seems more likely that chronic hyperinsulinemia in insulin-resistant individuals acts to increase adipose tissue leptin synthesis and secretion, leading to higher ambient leptin concentrations.

Adult↗

PubMed1998

Further evidence for a central role of adipose tissue in the antihyperglycemic effect of metformin.

OBJECTIVE: To evaluate further the relative roles played by liver and adipose tissue in the therapeutic response to metformin in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 11 patients with diet-treated type 2 diabetes were given metformin for approximately 3 months. Measurements were made before and after treatment of 1) fasting and postprandial plasma glucose, insulin, and free fatty acid (FFA) concentrations; 2) glucose appearance (Ra) and disappearance (Rd) rates measured overnight with 3-[3H]glucose; and 3) plasma FFA concentrations during a 195-min infusion period at relatively low insulin (approximately 12-24 microU/ml) concentrations. RESULTS: Mean +/- SEM fasting plasma glucose concentration was significantly lower (175 +/- 11 vs. 224 +/- 15 mg/dl; P < 0.01) after treatment with metformin. Mean +/- SEM insulin concentrations measured from 8:00 A.M. to 5:00 P.M. did not change with treatment. However, both glucose and FFA concentrations were significantly lower (P < 0.01) when measured over the same time period, and the decreases in plasma FFA and glucose concentration were highly correlated (r = 0.81; P = 0.03). Overnight glucose turnover studies indicated that neither Ra (hepatic glucose production [HGP]) nor Rd changed significantly with treatment in association with metformin treatment. Since plasma glucose concentration was much lower after metformin treatment, the overnight glucose metabolic clearance rate (MCR) was significantly lower (P < 0.01). Finally, the ability of insulin to inhibit isoproterenol-stimulated increases in plasma FFA concentration was enhanced in metformin-treated patients (P < 0.05). CONCLUSIONS: Metformin treatment was associated with significantly lower fasting plasma glucose concentrations and lower day-long plasma glucose and FFA concentrations. Although overnight HGP was unchanged after treatment with metformin, the overnight glucose MCR was significantly increased, and the antilipolytic activity of insulin was also enhanced. Given these findings, it is suggested that at least part of the antihyperglycemic effect of metformin is due to a decrease in release of FFA from adipose tissue, leading to lower circulating FFA concentrations and an increase in glucose uptake.

Adipose Tissue↗

PubMed1997

EBV binds to lymphocytes of transgenic mice that express the human CR2 gene.

Epstein Barr virus (EBV) is unable to bind to or infect normal mouse lymphocytes. A construct containing the human complement receptor type 2 (CR2) gene, the receptor for EBV, was placed under the control of the IgH/c-fos enhancer/promoter and microinjected into single cell embryos. A total of five transgenic mouse lines were established and four expressed hCR2 mRNA. Flow cytometry and immunostaining revealed that approximately 15-30% of the lymphocytes from the thymus, spleen and lymph nodes expressed hCR2 protein on their surface and bound EBV. Despite this binding, less than 1% of the cells showed evidence that the virus was internalized or replicated. Transgenic mouse lymphocytes, expressing hCR2, could not be immortalized with EBV. It is concluded that the simple expression of hCR2 receptor on mouse lymphocytes is not sufficient for efficient infection.

Animals↗

PubMed1997

Insulin resistance does not change the ratio of proinsulin to insulin in normal volunteers.

Plasma glucose, insulin, and proinsulin concentrations were measured before and after an oral glucose challenge in 57 nondiabetic individuals. In addition, insulin-mediated glucose disposal was estimated by determining the steady state plasma glucose (SSPG) concentration after a 180-min iv infusion of somatostatin, insulin, and glucose. The plasma glucose concentration after oral glucose administration was used to divide the population into those with normal (n = 36) or impaired glucose tolerance (IGT; n = 21), and the 36 normal glucose-tolerant individuals were further subdivided into an insulin-sensitive (SSPG, < 9.0 mmol/L; n = 15) and an insulin-resistant (SSPG, > 10 mmol/L; n = 21) group. Fasting and postglucose load insulin concentrations were similar in the normal glucose-tolerant insulin-resistant and IGT groups, but were significantly higher (P < 0.02- < 0.001) than those in normal glucose-tolerant insulin-sensitive individuals. Fasting proinsulin concentrations were also higher (P < 0.002) in the normal glucose-tolerant insulin-resistant (15.1 +/- 1.5 pmol/L) and IGT (15.8 +/- 1.8 pmol/L) groups compared to those in normal glucose-tolerant insulin-sensitive volunteers (9.3 +/- 1.2 pmol/ L). However, the ratio of fasting proinsulin to insulin was identical in all three groups (0.12). When the three groups were combined, significant relationships (P < 0.001) existed between SSPG (degree of insulin resistance) and both fasting proinsulin (r = 0.59) and insulin (r = 0.66) concentrations, but not with the ratio of proinsulin to insulin (r = 0.03). These results demonstrate that fasting proinsulin and insulin concentrations are increased in insulin-resistant, nondiabetic subjects, and the more insulin resistant, the greater the increase. In contrast, the ratio of proinsulin to insulin did not vary as a function of insulin resistance. Thus, neither insulin resistance nor the need to secrete more insulin to maintain glucose tolerance necessarily leads to abnormal insulin processing by the beta-cell.

Administration, Oral↗

PubMed1997

Results of a placebo-controlled study of the metabolic effects of the addition of metformin to sulfonylurea-treated patients. Evidence for a central role of adipose tissue.

OBJECTIVE: To define the metabolic effects of metformin in the treatment of NIDDM and to evaluate potential mechanisms for its ability to improve glycemic control. RESEARCH DESIGN AND METHODS: Sulfonylurea-treated patients, with inadequate glycemic control, were treated with metformin in either a placebo-controlled or open fashion. Measurements were made of 1) fasting and postprandial plasma glucose, insulin, and free fatty acid (FFA) concentrations; 2) glucose appearance and disappearance rates measured overnight with 3-[3H]glucose; and 3) plasma FFA concentrations during a 45-min infusion period at relatively low (approximately 60 pmol/l) insulin concentrations. RESULTS: Mean +/- SE hourly plasma glucose, insulin, and FFA concentrations were similar before and after treatment in the placebo group. In contrast, mean hourly plasma glucose concentrations were significantly lower (P < 0.005) after metformin treatment in both the placebo-controlled and open-label groups (-3.9 +/- 1.0 and -4.4 +/- 0.8 mmol/l, respectively). Similarly, day-long hourly FFA levels were lower (P < 0.005) following metformin in the placebo-controlled and open-label groups (-87 +/- 35 and -136 +/- 31 mumol/l, respectively). Plasma insulin concentrations did not change with treatment in any group. Overnight glucose turnover studies indicated that neither the rate of glucose appearance (hepatic glucose production) or glucose disappearance changed significantly with treatment in the placebo or metformin groups. Because plasma glucose concentration was much lower after metformin treatment, overnight glucose metabolic clearance rate was significantly (P < 0.001) lower in this group. Finally, plasma FFA concentrations in response to a low-dosage insulin infusion (5 mU.m-2.min-1) were significantly lower after metformin as compared with the placebo-treated group (P < 0.001). CONCLUSIONS: Metformin treatment was associated with significantly lower day-long plasma glucose and FFA concentrations. Although overnight hepatic glucose production was unchanged following treatment with metformin, the overnight glucose metabolic clearance rate significantly increased. Given these findings, it is suggested that at least part of the antihyperglycemic effect of metformin is due to an increase in glucose uptake, secondary to a decrease in release of FFA from adipose tissue, and lower circulating FFA concentrations.

Adipose Tissue↗

PubMed1997

Adherence of mononuclear cells to endothelium in vitro is increased in patients with NIDDM.

OBJECTIVE: To compare the binding to cultured endothelial cells of mononuclear cells isolated from healthy volunteers and patients with NIDDM. RESEARCH DESIGN AND METHODS: Mononuclear cells were isolated from healthy volunteers (n = 11) and patients with NIDDM (n = 14) and incubated with ECV 304 cells, a human umbilical endothelial cell-derived transformed cell line. Following a period of incubation, the adherence of mononuclear cells to endothelial cells was determined. RESULTS: Adherence of mononuclear cells from patients with NIDDM was significantly greater (P < 0.05) than that of cells isolated from the healthy volunteers, and this difference persisted when adjusted for age, sex, and degree of obesity. Mononuclear cell binding to ECV 304 cells correlated significantly with fasting plasma glucose (r = 0.52, P < 0.01), insulin (r = 0.51, P < 0.01), triglyceride (r = 0.54, P < 0.01), and VLDL (r = 0.54, P < 0.01) and HDL cholesterol (r = -0.45, P < 0.05) levels, but not with either total or LDL cholesterol levels or blood pressure. CONCLUSIONS: Since the adherence of mononuclear cells to the endothelium represents the earliest step in atherogenesis, the observation that mononuclear cells from patients with NIDDM bind more avidly to cultured endothelial cells may help explain why accelerated atherosclerosis occurs in patients with NIDDM. The metabolic abnormality, or abnormalities, present in patients with NIDDM that is responsible for the enhanced adhesiveness of mononuclear cells requires further examination.

Cell Adhesion↗

PubMed1995

Phenotype and frequency of cells secreting IL-2, IL-4, IL-6, IL-10, IFN and TNF-alpha in human peripheral blood.

The phenotype and frequency of cells in normal human peripheral blood spontaneously secreting IL-2, IL-4, IL-6, IL-10, IFN and TNF-alpha ex vivo was determined using ELIspot assays. CD4+ T cells were the dominant source of IL-2 and IL-4 while multiple cell types (primarily CD8+ lymphocytes) produced IFN. Fewer than 0.05% of mononuclear cells were spontaneously secreting these T cell derived factors. By comparison, IL-6, IL-10 and TNF-alpha were produced by 0.7-20% of PBMC. The primary sources of the latter cytokines were CD14+ macrophages/monocytes. A significant positive correlation was found in the frequency of cells secreting IL-6, IL-10 and TNF-alpha ex vivo, suggesting that the release of such factors was coordinately regulated. No such correlation was found among IL-2, IL-4 and IFN secreting cells, indicating that the production of predominantly T cell derived cytokines was regulated independently.

Antigens, CD↗