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Biomedical subjects

B Zinman

Publications and source records attributed to B Zinman.

At least 109 records · Page 6Linked to original sources
PubMed1996

Hepatic glucose production is regulated both by direct hepatic and extrahepatic effects of insulin in humans.

The present study examines the effect of the route of insulin delivery on glucose turnover in humans. By using a new noninvasive in vivo method, the acute effect of insulin secreted by the pancreas can be compared with that of insulin delivered by a peripheral vein. Three euglycemic-hyperinsulinemic studies were performed in lean healthy men. In the first study (n = 10), constant portal hyperinsulinemia was produced using a programmed intravenous tolbutamide infusion algorithm, and the insulin secretion rate was mathematically derived by deconvolution from peripheral plasma C-peptide levels. In the second study (n = 10), exogenous insulin was infused by peripheral vein at the same rate as that determined in the first study. In the third study (n = 7), the peripheral insulin levels in the first study were matched by infusing exogenous insulin into a peripheral vein at half that rate. Peripheral insulin levels were higher (P < 0.001) with the full-rate peripheral insulin infusion (266.3 +/- 28.1 pmol/l) than with the portal delivery of insulin (171.1 +/- 30.4 pmol/l) or the half-rate peripheral insulin infusion (158.6 +/- 7.4 pmol/l) (portal versus half-rate peripheral insulin infusion, NS). Calculated hepatic insulin levels were higher (P < 0.001) in the portal insulin study (443.1 +/- 52.6 pmol/l) than in the full-rate peripheral insulin study (303.6 +/- 30.9 pmol/l) or in the half-rate peripheral insulin study (204.5 +/- 9.8 pmol/l). Hepatic glucose production (HGP) was suppressed to a greater extent with the full-rate peripheral insulin infusion (69.3 +/- 7.8%, P < 0.001 vs. portal or half-rate peripheral insulin) than portal (50.3 +/- 9.8%) or half-rate peripheral insulin infusion (36.8 +/- 3.8%). In the portal insulin study, however, suppression was greater than in the half-rate peripheral insulin study (P < 0.01), in spite of equal peripheral insulin levels. The assumption that tolbutamide, when used in this fashion, has no independent effect on glucose turnover, glucagon, or gluconeogenic precursor and energy substrates for gluconeogenesis was validated in five C-peptide-negative patients with IDDM. We conclude that in nondiabetic humans, 1) peripheral effects of insulin are important in suppressing HGP, as evidenced by the greater suppression of HGP with equivalent rate peripheral versus portal insulin delivery, and 2) because HGP was suppressed to a greater extent with portal verus peripheral insulin delivery at half the rate when peripheral insulin levels were matched, insulin-induced suppression of HGP is also partly mediated by a direct hepatic effect.

Adult↗
PubMed1996

Rationale and design of a large study to evaluate the renal and cardiovascular effects of an ACE inhibitor and vitamin E in high-risk patients with diabetes. The MICRO-HOPE Study. Microalbuminuria, cardiovascular, and renal outcomes. Heart Outcomes Prevention Evaluation.

OBJECTIVE: To describe the rationale and design of a large international study (microalbuminuria, cardiovascular, and renal outcomes [MICRO] in the HOPE [Heart Outcomes Prevention Evaluation] study) of an ACE inhibitor and vitamin E for the prevention of diabetic nephropathy (DN) and cardiovascular disease (CVD) in patients with diabetes and microalbuminuria (MA). RESEARCH DESIGN AND METHODS: A total of 3,657 diabetic subjects, including 1,129 with MA, are randomly allocated to receive the ACE inhibitor ramipril (or placebo) and vitamin E (or placebo) for 4 years in a two-by-two factorial design. Diabetic subjects are a subset of the 9,541 subjects enrolled in the HOPE study. RESULTS: The development of DN in microalbuminuric diabetic subjects and the development of MA in normoalbuminuric subjects, as well as cardiovascular death, myocardial infarction, and storke, are the main outcomes. The correlation of changes in albuminuria with changes in carotid atherosclerosis documented in a subset of subjects will also be analyzed. CONCLUSIONS: The effect of both an ACE inhibitor and vitamin E on the progression of renal and CVD in patients with diabetes is being assessed in the MICRO-HOPE study.

Albuminuria↗
PubMed1996

Efficacy of feedback from quarterly laboratory comparison in maintaining quality of a hospital capillary blood glucose monitoring program.

OBJECTIVE: A 1-year randomized prospective study was conducted to investigate the efficacy of feedback from split-sample testing as part of a capillary blood glucose quality assurance program. RESEARCH DESIGN AND METHODS: A total of 124 nurses were randomized to either group A (quarterly comparisons with feedback) or group B (no feedback). The measure of nurse accuracy against the laboratory at 0, 6, and 12 months was determined by an additional five to seven split-sample tests without giving feedback to either group. Mean accuracy was determined in terms of percent absolute deviation from the laboratory result and a clinical consensus limit of +/- 20% deviation from the laboratory. RESULTS: By 12 months, there was a significant effect of feedback on nurse agreement with the laboratory method (P = 0.022 when agreement was scored as the mean percent absolute difference and P = 0.002 when agreement was scored in terms of the +/- 20% clinical consensus limit). Nurses in the group who had received no quarterly feedback from split-sample testing produced a 3.5% greater mean percent absolute deviation from the laboratory method and 12% fewer comparisons within the acceptable +/- 20% range. CONCLUSIONS: Feedback received from split-sample testing has a significant effect in maintaining accuracy in capillary blood glucose monitoring.

Blood Glucose↗
PubMed1994

Regulation of glucose transport and expression of GLUT3 transporters in human circulating mononuclear cells: studies in cells from insulin-dependent diabetic and nondiabetic individuals.

We have previously shown that human circulating mononuclear cells (CMCs) respond to physiological concentrations of insulin with a rapid increase in glucose transport rate. The responding cells were found to be the monocytes, and cells derived from individuals with insulin-dependent diabetes mellitus (IDDM) had lower basal and insulin-stimulated glucose transport rates. Of interest, both cell types were found to express the GLUT1 but not the typical insulin-responsive GLUT4 transporter isoform. To further study the mechanisms responsible for stimulation of transport in these cells, we investigated (1) the response to insulin-like growth factor-I (IGF-I) and insulin-mimetic agents, and (2) the expression of other glucose transporter isoforms in CMCs of nondiabetic and IDDM individuals. The time course of insulin-stimulated glucose uptake in CMCs was rapid, reaching a plateau within 30 minutes. CMCs showed a dose-dependent and highly sensitive increase in glucose uptake to IGF-I (maximal response reached at 0.1 to 0.5 nmol/L IGF-I). The IGF-I dose-response curve was similar for CMCs of control and IDDM individuals, but both the basal and maximal response to IGF-I were lower in the diabetic group (P < .01). CMCs did not respond to vanadate, lithium, hydrogen peroxide, or short incubation (1 hour) with metformin, but glucose uptake increased in response to peroxides of vanadate and longer-duration (14 hours) metformin incubations. The glucose transporter isoforms of separated monocytes and lymphocytes were further investigated by Northern blotting of total RNA with a GLUT3-specific cDNA probe and by Western blotting of total membranes using GLUT3-specific antiserum.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

VLDL production is decreased to a similar extent by acute portal vs. peripheral venous insulin.

Acute changes in very low-density lipoprotein (VLDL) triglyceride (TG) and VLDL apolipoprotein (apo) B production were examined in 11 healthy young males in response to insulin delivered either by the peripheral venous route or secreted directly by the pancreas. Steady rates of pancreatic insulin secretion were achieved for 5 h by a programmed intravenous tolbutamide infusion, while euglycemia was maintained with a dextrose infusion. Insulin secretory rate was calculated from peripheral C-peptide levels by deconvolution, and, in a subsequent study, exogenous insulin was infused peripherally to match this pancreatic insulin secretory rate in each subject. Changes in VLDL TG and VLDL apo B production were determined semiquantitatively on each occasion by examining the change in slope of the specific activity (SA) of 3H-labeled triglyceride glycerol ([3H]TGG) and 131I-VLDL apo B vs. time curves, respectively, occurring with acute hyperinsulinemia. Plasma-free fatty acids (FFA), TG, apo B, and VLDL TG/VLDL apo B ratio decreased to a similar extent in both studies after the onset of hyperinsulinemia. VLDL TG production decreased significantly in both the tolbutamide (-47.1 +/- 7.3%, P < 0.002) and the exogenous insulin infusion study (-52.8 +/- 12.4%, P < 0.005). VLDL apo B production also decreased significantly in both studies (-58.9 +/- 7.5%, P = 0.0007 and -52.1 +/- 6.8%, P < 0.006, respectively), and there were no significant differences between studies. Tolbutamide was shown to have no independent effect on VLDL TG or VLDL apo B production in four insulin-deficient diabetic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Abnormalities in the renal and vascular responses to LBNP in humans with early diabetes.

Plasma atrial natriuretic factor (ANF) concentrations are increased in subjects with insulin-dependent diabetes mellitus (IDDM). A potential contribution of ANF to the maintenance of abnormalities in renal hemodynamic function has been considered but not proven in human diabetic subjects. The aim of these experiments was to determine the response of renal blood flow (RBF), glomerular filtration rate (GFR), filtration fraction (FF), and urinary sodium excretion (UNaV) to a reduction of plasma ANF concentrations induced by application of nonhypotensive lower body negative pressure (LBNP) in a group of subjects with early, uncomplicated, well-controlled IDDM compared with control subjects. Baseline supine measurements before LBNP revealed the diabetic subjects to have a significantly higher plasma ANF (31 +/- 2 vs. 24 +/- 2 pg/ml, P = 0.05). GFR tended to be higher (118 +/- 11 vs. 104 +/- 9 ml/min) and UNaV tended to be depressed (188 +/- 25 vs. 240 +/- 25 mumol/min) despite equal sodium intake, but not significantly so. In addition IDDM subjects exhibited significantly lower baseline plasma norepinephrine (PNE) concentrations (0.91 +/- 0.20 vs. 1.60 +/- 0.2 nmol/l, P = 0.03). Forearm vascular resistance (FVR) was not significantly different between the two groups (29 +/- 5 vs. 33 +/- 5 units). LBNP induced comparable decreases in ANF and central venous pressure (CVP) in both groups. The anticipated renal response to ANF reduction (declines in GFR, FF, and UNaV) occurred only in the normal control group. The percent decline in GFR (11% vs. 34.5%, P = 0.01) was markedly attenuated in IDDM subjects. The expected reflexive increase in PNE and FVR also did not occur in IDDM subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Insulin blunts the natriuretic action of atrial natriuretic peptide in hypertension.

Hyperinsulinemia and insulin resistance are implicated in the etiology of hypertension, but the mechanisms involved have not been established. The objectives of this study were to determine whether untreated essential hypertensive patients are more sensitive to the antinatriuretic action of insulin and more resistant to the counteracting natriuretic effect of atrial natriuretic peptide in contrast to age- and sex-matched normotensive control subjects. Urinary sodium excretion was measured at baseline, during hyperinsulinemic euglycemic clamp, and during coadministration of insulin and atrial natriuretic peptide. Baseline urinary sodium excretion was not significantly different in the normotensive subjects (415 +/- 47 mumol/min, n = 12) and hypertensive patients (381 +/- 18 mumol/min, n = 10); with the institution of insulin infusion, there was a similar and significant decline from baseline (P < .001) to 289 +/- 35 mumol/min in normotensive subjects and 235 +/- 17 mumol/min in hypertensive patients. Atrial natriuretic peptide was able to oppose the antinatriuretic action of insulin in normotensive subjects, increasing urinary sodium excretion significantly to a mean level of 352 +/- 31 mumol/min (P < .05), which did not differ significantly from baseline. In the hypertensive group, atrial natriuretic peptide infusion had no effect on urinary sodium excretion (238 +/- 18 mumol/min), and the difference from baseline remained highly significant (P < .001). The hypertensive patients were significantly less insulin sensitive than their normotensive counterparts, as reflected by a lower glucose utilization rate and higher mean baseline plasma insulin level (P < .05 for each).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

A new method for comparing portal and peripheral venous insulin delivery in humans: tolbutamide versus insulin infusion.

We describe a new noninvasive method for comparing insulin secreted acutely by the pancreas vs. a matched peripheral venous insulin infusion in humans. An intravenous tolbutamide infusion algorithm was developed that produced sustained steady rates of portal insulin secretion over 5 h in 11 healthy young men. Plasma glucose levels were maintained in the euglycemic range by adjusting the rate of an iv dextrose (20%) infusion. The pancreatic insulin secretory rate was calculated from peripheral C-peptide levels by deconvolution using standard parameters for a two-compartment mathematical model for C-peptide distribution and metabolism. On a subsequent occasion in the same subject, exogenous insulin was infused peripherally at a rate that matched the earlier tolbutamide-induced pancreatic insulin secretory rate, and euglycemia was maintained with a variable 20% dextrose infusion. The assumption that tolbutamide, when used in this fashion, has no independent insulin-like or insulin-potentiating effect at either low or high levels of peripheral insulinemia, does not affect insulin clearance, and does not suppress peripheral glucagon levels was validated in four patients with insulin-dependent diabetes mellitus. Mean peripheral immunoreactive insulin was significantly higher in the insulin infusion study than in the tolbutamide study (286 +/- 31 vs. 156 +/- 21 pmol/L; P = 0.0001). The dextrose infusion rates required to maintain euglycemia were also higher in the insulin infusion study (0.44 +/- 0.03 vs. 0.32 +/- 0.03 mmol/kg.min; P = 0.003). The MCR of insulin was greater in the tolbutamide infusion vs. the exogenous insulin infusion study (32.6 +/- 2.9 vs. 19.8 +/- 2.2 mL/kg.min; P = 0.0003), probably due to the hepatic first pass effect on insulin clearance when insulin is delivered by the portal route. This noninvasive method can be used in future studies to examine the relative importance of direct hepatic vs. peripheral effects of insulin in controlling hepatic glucose and lipid production.

Adult↗
PubMed1994

The use of bioelectrical impedance analysis (BIA) to estimate body composition in the Diabetes Control and Complications Trial (DCCT).

Although weight gain often accompanies intensive treatment regimens designed to achieve near-normal glycemia in insulin-dependent diabetes mellitus (IDDM), body composition (BC) has not been well studied. Bioelectrical impedance analysis (BIA) is a safe, rapid, and non-invasive method of assessing BC but has not been utilized widely in IDDM. Data from 46 adults with IDDM were used to develop a regression model estimating fat-free body mass (FFM) from bioimpedance measurements obtained using a proximal electrode placement. Reference values of FFM were determined by dual x-ray absorptiometry (DXA). A model using the ratio of height squared to the minimum resistance of 4 limb-lead combinations (H2/R), total body weight, and a weight-gender interaction achieved a high level of accuracy (R2 = 0.982, residual standard deviation = 1.43 kg), while studies of 10 subjects before and after a light meal found no short-term effect of glycemia on measured BIA variables. BIA will therefore be used in combination with waist-to-hip ratios to study the composition and distribution of the increased weight associated with intensive therapy in the DCCT.

Absorptiometry, Photon↗
PubMed1993

Atrial natriuretic factor counteracts sodium-retaining actions of insulin in normal men.

It has been hypothesized that hyperinsulinemia is causally related to hypertension by its effect on renal sodium transport. To examine the relationship between the sodium-retaining actions of insulin and atrial natriuretic factor (ANF), 16 healthy subjects were studied on three occasions, approximately 1 wk apart, using standard clearance techniques to evaluate responses during the acute administration of insulin, low-dose ANF, or both. In study 1, the euglycemic clamp was used to increase plasma insulin 10-fold to an average of 320 +/- 14 (SE) pM. This maneuver produced an immediate and persistent fall in sodium excretion from 0.315 +/- 0.02 to 0.207 +/- 0.02 mmol/min (P < 0.001) independent of change in renal hemodynamics, lithium clearance, and catecholamines. The decline in sodium excretion was associated with a marked increase in fractional distal sodium reabsorption. Systolic and diastolic pressure did not change significantly. In study 2, low-dose ANF (0.3 pmol.kg-1.min-1) designed to raise plasma levels to twice baseline was administered simultaneously in a repeat of study 1. This maneuver abolished insulin-mediated sodium reabsorption. In study 3, low-dose ANF infusion alone produced no changes in tubular handling of sodium. Our findings indicate that insulin at levels found in hyperinsulinemic states caused sodium retention and that physiological increases in plasma ANF concentration abolished the sodium-retaining action of insulin. Our findings suggest that if hypertension is causally related to hyperinsulinemia, mechanisms besides renal sodium retention are responsible for the hypertensive properties of insulin.

Adult↗
PubMed1993

Factors determining glucose tolerance in patients with thalassemia major.

To better understand the pathophysiology of glucose intolerance secondary to iron overload in patients with thalassemia major, we performed tolbutamide-modified frequently sampled iv glucose tolerance tests (FSIGTs) in 10 thalassemic patients (6 males and 4 females; 21.7 +/- 1.2 yr old; body mass index, 19.7 +/- 0.6 kg/m2) and 10 healthy controls (5 males and 5 females; 22.4 +/- 1.3 yr; body mass index, 20.6 +/- 0.5 kg/m2). Insulin secretion and action were quantified by application of the minimal model of glucose kinetics and the combined model of insulin and C-peptide kinetics to the FSIGT data. The insulin sensitivity index was significantly lower in thalassemia patients [72 +/- 12 min-1(nmol/mL)] compared to controls [158 +/- 21 min-1(nmol/mL); P = 0.0026]. The integrated insulin response during the FSIGT was significantly greater in thalassemia patients than in controls after tolbutamide injection (P = 0.042). The difference in insulin levels was apparently due to reduced hepatic insulin extraction in thalassemia (78 +/- 2% vs. 68 +/- 3%; P = 0.0251). Seven of the 10 thalassemia patients were studied prospectively at 6-month intervals for 6-12 months. Repeated measures analysis of variance indicated that across a 6-month interval, there was a decrease in the total integrated insulin response (P = 0.002), with no change in insulin sensitivity (P = 0.86). In conclusion, patients with thalassemia major have significant insulin resistance, which may be compensated for by an elevated circulating insulin level. The elevated insulin level in response to tolbutamide appears to be due to reduced hepatic extraction of insulin and not to an enhanced insulin secretory response. Over time, patients with thalassemia experience a reduction in their circulating insulin levels. Persistent insulin resistance along with a progressive reduction in circulating insulin levels may lead to glucose intolerance and diabetes mellitus, which have a high prevalence in patients with thalassemia major.

Adolescent↗
PubMed1992

Insulin-stimulated glucose transport in circulating mononuclear cells from nondiabetic and IDDM subjects.

The objectives of this study were 1) to evaluate glucose transport and its regulation by insulin in easily accessible human cells, 2) to investigate the glucose transporter isoforms involved, and 3) to establish whether a defect in glucose transport is associated with peripheral insulin resistance, which is common in insulin-dependent diabetes mellitus (IDDM) patients. We measured 2-deoxyglucose (2-DG) uptake in circulating mononuclear cells from 23 nondiabetic adults, 16 adults with IDDM, and 10 children with IDDM. Circulating mononuclear cells were separated from whole blood by Ficoll gradients and incubated with +/- 1 nM insulin. 2-DG uptake was measured after incubation with [3H]2-DG and cell separation through corn oil-phthalate. Cytochalasin B-inhibitable 2-DG uptake (basal and insulin stimulated) was higher in control than in IDDM subjects (P less than 0.001). Insulin significantly increased 2-DG uptake or 3-O-methylglucose uptake in both groups. Basal and insulin-stimulated 2-DG uptake was similar for adults and children with IDDM and did not correlate with age or body mass index in any group or disease duration, insulin dosage, or HbA1c in IDDM. In separated monocytes and lymphocytes, 2-DG uptake increased in response to insulin only in the monocyte population. Insulin dose-response curves indicated maximal stimulation of hexose uptake at 1-2 nM insulin for both control and diabetic subjects and demonstrated a significant decrease in maximal insulin response in the latter. Immunoblotting with specific antibodies revealed that circulating mononuclear cells and separated monocytes express the GLUT1 but not the GLUT4 isoform of the glucose transporter.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Insulin resistance and action in hypertriglyceridemia.

To define further the characteristics of insulin insensitivity associated with hypertriglyceridemia, the metabolic responses to the euglycemic insulin clamp were evaluated in 6 hypertriglyceridemic male patients and compared to 5 normal male controls. At baseline, the hypertriglyceridemic patients had elevated triglycerides (687 +/- 172 vs 78 +/- 7 mg/dl, P less than 0.005) and free fatty acids (702 +/- 36 vs 444 +/- 42 microM/l, P less than 0.005) concentrations. During the euglycemic insulin clamp, steady-state plasma glucose concentrations were similar in both groups (90.2 +/- 1.5 vs 88.8 +/- 2.3 mg/dl, ns) as were steady state insulin levels (142 +/- 10.1 vs 132.2 +/- 6.8 microU/ml**). The amount of glucose metabolized during the last hour of the clamp (M) was significantly reduced in the hypertriglyceridemic patient (2.9 +/- 0.4 vs 6.2 +/- 0.7 mg.min-1.kg-1, P less than 0.001). Changes in free fatty acid, glycerol, B-hydroxybutyrate, lactate and pyruvate during the euglycemic insulin clamp were similar indicating a preserved antilipolytic, antiketogenic and glycolytic intermediate (lactate + pyruvate) response to insulin and glucose infusion in the hypertriglyceridemic patients. In summary, hypertriglyceridemia is associated with insulin resistance as it relates to muscle glucose utilization. However, this is not universal, as a number of other insulin responsive pathways appear to be unaffected.

3-Hydroxybutyric Acid↗
PubMed1990

Growth hormone suppression and nonproliferative diabetic retinopathy: a preliminary feasibility study.

We used the long acting somatostatin analogue SMS 201-995 in order to examine the feasibility and effect of medical suppression of growth hormone in nonproliferative diabetic retinopathy. Six insulin-dependent diabetic subjects with nonproliferative retinopathy were studied. After eight weeks of SMS 201-995 administration, 24-hour integrated plasma growth hormone concentrations had declined by 47.0 +/- 9.3% of pretreatment values (p less than 0.01), and insulin requirements fell from 40.7 +/- 6.7 units per day to 32.2 +/- 6.9 units per day (p less than 0.01). Plasma levels of somatomedin-C were low before SMS 201-995 (0.5 +/- 0.1 U/ml) and remained unchanged at eight weeks (0.6 +/- 0.1 U/ml; p = ns). During SMS 201-995 administration, best corrected visual acuity improved in both right eyes (53.8 +/- 2.57 to 59.8 +/- 0.7 letters, p less than 0.05) and left eyes (54.8 +/- 2.8 to 61.7 +/- 1.23 letters, p less than 0.03). Fluorescein angiography and stereo fundus photography demonstrated concurrent improvement in retinopathy level in only two subjects. Following cessation of SMS 201-995 treatment, visual acuity returned to pretreatment levels in both right eyes (54.5 +/- 2.4 letters, p = ns compared to baseline) and left eyes (55.8 +/- 2.6 letters, p = ns compared to baseline). These results demonstrate that growth hormone was only partially suppressed by SMS 201-995 in insulin-dependent diabetic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗