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Papers by Marla Smith

Journal of the American Geriatrics Society, 1997

This study was undertaken to understand the dynamics of glucose metabolism in healthy non-diabeti... more This study was undertaken to understand the dynamics of glucose metabolism in healthy non-diabetic subjects older than age 80 (old-old) compared with subjects aged 61 to 79 (young-old), as well as to compare healthy older subjects with impaired glucose tolerance (IGT) with older subjects with normal glucose tolerance (NGT). A cross sectional, observational study. A university hospital clinical research center. There were 28 community-dwelling adults, 10 older than age 80 and 18 aged 61 to 79. Thirteen of these people had NGT and 15 had IGT. Subjects were not taking any medication that interfered with glucose tolerance. Status of glucose tolerance was determined by an oral glucose tolerance test categorized as NGT or IGT according to WHO criteria. Insulin sensitivity (SI) and glucose effectiveness (SG) were assessed using a tolbutamide-assisted intravenous glucose tolerance test (IVGTT). The data were analyzed using the Minmod modeling program. Glucose tolerance (K(g)) and the acute ...

The American journal of physiology, 1994

This study was designed to define the effect of human aging on hypoglycemia counterregulatory mec... more This study was designed to define the effect of human aging on hypoglycemia counterregulatory mechanisms. A hyperinsulinemic (2 mU.kg-1.min-1) glucose clamp procedure was used to control glucose and insulin levels during stepwise lowering of plasma glucose. Counterregulatory hormones, hepatic glucose production (HGP), glucose utilization, and symptoms of hypoglycemia were studied in 13 healthy young [age 24 +/- 1 (SE) yr] and 11 healthy old (age 65 +/- 1 yr) nondiabetic volunteers on two occasions: 1) at matched euglycemia and 70 and 60 mg/dl (study 1) and 2) at matched euglycemia and 60 and 50 mg/dl (study 2). The old had consistently lower epinephrine (P < 0.005), glucagon (P < 0.02), cortisol (P < 0.05), and pancreatic polypeptide (P < 0.02) responses at the 60-mg/dl glucose step in study 1. However, these differences were no longer detectable at the more severe hypoglycemic stimulus of 50 mg/dl in study 2. A consistent increase in HGP occurred in both groups only at ...

The American journal of physiology, 1989

Mononuclear leukocyte (MNL) beta 2-adrenergic receptor (beta 2-AR) binding and its linked adenyla... more Mononuclear leukocyte (MNL) beta 2-adrenergic receptor (beta 2-AR) binding and its linked adenylate cyclase sensitivity to isoproterenol were measured in nine healthy humans prior to and after 7 days of dietary sodium restriction to determine whether chronic physiological increases in plasma norepinephrine (NE) are associated with the downregulation of beta-AR-mediated function. Sodium restriction resulted in an increase in the plasma NE concentration (P less than 0.02) and decreases in MNL beta 2-AR density (P less than 0.001), affinity for antagonist (P less than 0.001), and adenylate cyclase sensitivity to isoproterenol (ANOVA, P less than 0.01). To determine whether this downregulation of MNL beta 2-AR-mediated function is related to the increased plasma NE concentration or to increased extravascular NE release, NE kinetics was assessed using compartmental analysis in each subject prior to and after sodium restriction. Sodium restriction caused a decrease in the plasma NE metabo...

The Journal of pharmacology and experimental therapeutics, 1990

These studies were undertaken to examine the contribution of central nervous system mechanisms to... more These studies were undertaken to examine the contribution of central nervous system mechanisms to the cardiovascular and sympathoadrenal effects of cocaine. Changes in systolic and diastolic blood pressure, heart rate and plasma catecholamine concentrations were determined in response to cocaine injected i.a. or i.c.v. in conscious unrestrained rats. Systemically administered cocaine produced brisk, transient dose-related increases in systolic and diastolic pressure at doses of 0.05 to 5 mg/kg i.a. Plasma catecholamine concentrations increased in a dose-related manner, reaching peak levels at 5 to 10 min after i.a. cocaine injection. Only the higher doses of cocaine induced reflex vagal bradycardia that was blocked by atropine (0.4 mg/kg i.a.). Propranolol (1 mg/kg i.a.) prolonged the duration of cocaine-induced hypertension and bradycardia. Ganglionic blockade with chlorisondamine (7.5 mg/kg i.a.) antagonized completely the cardiovascular and sympathoadrenal effects of cocaine, ind...

The American journal of physiology, 1990

We used compartmental analysis to study the influence of age on the kinetics of norepinephrine (N... more We used compartmental analysis to study the influence of age on the kinetics of norepinephrine (NE) distribution and metabolism. Plasma NE and [3H]NE levels were measured in 10 young (age 19-33 yr) and 13 elderly (age 62-73 yr) subjects in the basal supine position, during upright posture, and after 1 wk of a sodium-restricted diet. We found that the basal supine release rate of NE into the extravascular compartment, which is the site of endogenous NE release (NE2), was significantly increased in the elderly group (young, 9.6 +/- 0.5; elderly, 12.3 +/- 0.8 nmol.min-1.m-2; means +/- SE; P = 0.016), providing direct evidence for an age-related increase in sympathetic nervous system (SNS) tone. Although upright posture led to a greater increase in plasma NE in the young (0.90 +/- 0.07 to 2.36 +/- 0.16 nM) than in the elderly (1.31 +/- 0.11 to 2.56 +/- 0.31 nM; age group-posture interaction, P = 0.02), the increase in NE2 was similar between the young (9.6 +/- 0.6 to 16.2 +/- 1.5 nmol.m...

The American journal of physiology, 1991

To determine whether differences in neuronal reuptake contribute to age-related changes of sympat... more To determine whether differences in neuronal reuptake contribute to age-related changes of sympathetic nervous system activity, we compared norepinephrine (NE) release and metabolism during [3H]NE infusion and decay in six young (age 19-26 yr) and seven older (age 61-73 yr) healthy nonobese subjects. Subjects were studied on a control day and on a separate day after desipramine (DMI; 125 mg orally), a neuronal reuptake blocker. Compartmental analysis of plasma NE specific activity was used to determine several NE kinetic parameters. Plasma NE levels and NE spillover rates were higher in the elderly. Although plasma NE was unaffected by DMI in both age groups, both the metabolic clearance rate of NE from plasma and the rate of NE spillover into plasma fell in young and older groups during DMI. Furthermore, DMI dramatically lowered the mass of NE in the extravascular compartment and the rate of NE entry into the extravascular compartment. Thus neuronal uptake blockade has major effect...

The American journal of physiology, 1990

Beta-Adrenergic blockade with propranolol (PRP) has been reported to cause an increase in plasma ... more Beta-Adrenergic blockade with propranolol (PRP) has been reported to cause an increase in plasma norepinephrine (NE) levels in humans, which suggests that a reflex increase in sympathetic nervous system (SNS) vasoconstrictor tone compensates for the hypotensive effect of beta-adrenergic blockade. However, plasma NE levels are an indirect measure of SNS activity. We have developed a two-compartment model of NE kinetics to estimate NE release into an extravascular compartment as a more comprehensive measure of systemic SNS activity. To determine whether beta-adrenergic blockade alters extravascular NE release, we studied nine healthy subjects during sequential infusions of saline and PRP. During PRP infusion, there was an increase in plasma NE levels [1.03 +/- 0.13 to 1.27 +/- 0.21 (SE) nM; P = 0.05], but the extravascular NE release rate decreased significantly (15.5 +/- 1.6 to 9.2 +/- 1.2 nmol.min-1.m-2, P = 0.0002). The plasma NE concentration increased despite the fall in extravas...

Metabolism, 1991

We used MK-912, a potent new selective 4-adrenergic receptor antagonist that is active orally, to... more We used MK-912, a potent new selective 4-adrenergic receptor antagonist that is active orally, to study the effect of short-term, selective %-blockade on fasting plasma glucose (FPG) and pancreatic islet function in non-insulin-dependent diabetes (NIDDM). Ten asymptomatic patients with NIDDM received either a single oral dose of MK-912 (2 mg) or placebo in a double-blind, cross-over study. B-cell function was measured by the acute insulin response (AIR) to glucose (1.99 mmol/kg intravenously [Iv) and by the AIR to arginine (5 g IV) during a hyperglycemic glucose clamp at a mean glucose level of 32.1 mmol/ L to provide an estimation of maximal B-cell secretory capacity. A-cell function was estimated by the acute glucagon response (AGR) to arginine during the glucose clamp. Effective %-adrenergic blockade was apparently achieved, as there were substantial increases of plasma norepinsphrine (NE) (P < .Ol) and both systolic blood pressure (SBP) (P < .Ol) and diastolic blood pressure (DBP) (P < .05) after treatment with MK-912, but not after placebo. MK-912 caused a significant (P < .05) although modest decrease of FPG that was associated with a small increase of fasting plasma insulin (P < O.Ol), C-peptide (P < .05), and glucagon (P < .Ol). FPG and hormone levels remained unchanged after placebo. MK-912 tended to increase the AIR (P = 95) and the C-peptide response (P = .07) to glucose compared with placebo. There was a small, but significant, overall treatment effect for both the AIR and AGR to arginine with MK-912 (both P < .05, ANOVA). These studies indicate that MK-912 causes (1) sympathetic activation consistent with effective qadrenergic blockade; (2) a small decrease of FPG and a small increase of fasting plasma insulin; (3) a small improvement of B-cell function due to an increase in maximal B-cell secretory capacity; and (4) a small increase in basal and stimulated glucagon. These findings suggest that endogenous qadrenergic tone may contribute, although to a small extent, to the impaired B-cell function in NIDDM. If an q-blocker becomes available that does not increase BP, studies would be warranted to evaluate its potential impact on glucose regulation in patients with NIDDM.

Journal of Clinical Investigation, 1987

The present study was undertaken to quantify more precisely and to begin to address the problem o... more The present study was undertaken to quantify more precisely and to begin to address the problem of heterogeneity of the kinetics of distribution and metabolism of norepinephrine (NE) in humans, by using compartmental analysis. Steadystate NE specific activity in arterialized plasma during I3HINE infusion and postinfusion plasma disappearance of [3HINE were measured in eight healthy subjects in the supine and upright positions. Two exponentials were clearly identified in the plasma [HJNE disappearance curves of each subject studied in the supine (r = 0.94-1.00, all P < 0.01) and upright (r = 0.90-0.98, all P < 0.01) positions. A two-compartment model was the minimal model necessary to simultaneously describe the kinetics of NE in the supine and upright positions. The NE input rate into the extravascular compartment 2, estimated with the minimal model, increased with upright posture (1.87±0.08 vs. 3.25±0.2 pg/mm per Mi2, P < 0.001). Upright posture was associated with a fall in the volume of distribution of NE in compartment 1 (7.5±0.6 vs. 4.7+0.3 liters, P < 0.001), and as a result of that, there was a fall in the metabolic clearance rate of NE from compartment 1 (1.80±0.11 vs.

The Journal of Clinical Hypertension, 2010

The Journal of Clinical Endocrinology & Metabolism, 2006

Context: Studies in older people have shown inconsistent agreement between homeostasis model asse... more Context: Studies in older people have shown inconsistent agreement between homeostasis model assessment of insulin resistance (HOMA-IR) and dynamic measures of insulin action and have not evaluated HOMA β-cell. Objective: We compared measures of insulin sensitivity and β-cell function from the frequently sampled iv glucose tolerance test (FSIGT) to HOMA models. Design/Patients/Setting/Intervention: Two hundred fourteen young and old with normal glucose tolerance (NGT) and old with impaired glucose tolerance (IGT) participated in a retrospective analysis of FSIGT data in a university medical setting. Main Outcome Measure: Sensitivity to insulin (SI) and acute insulin response to glucose (AIRg) from FSIGT were compared with HOMA models. Results: SI and HOMA-IR measures identified similar patterns of increasing insulin resistance in the two older groups, compared with younger people with NGT, with the greatest degree of insulin resistance in older people with IGT (P < 0.05 vs. young...

The Journal of Clinical Endocrinology & Metabolism, 2006

Context: Glucose tolerance declines with age and may involve impaired β-cell sensitivity to gluco... more Context: Glucose tolerance declines with age and may involve impaired β-cell sensitivity to glucose and β-cell compensation for insulin resistance. Objective: We investigated β-cell sensitivity to glucose and β-cell compensation for nicotinic acid-induced insulin resistance in young (age <35 yr) people with normal glucose tolerance (NGT) and old (age >60 yr) people with NGT and impaired glucose tolerance (IGT). Design/Patients/Setting/Intervention: Fifteen young NGT, 16 old NGT, and 14 old IGT were randomized to 2-wk treatment with nicotinic acid or placebo in a double-blind, crossover study in a university medical setting. At the end of each treatment period, participants had a frequently sampled iv glucose tolerance test and ramp clamp, in which insulin secretion rates (ISR) were determined in response to a matched 5–10 mm glucose stimulus. Main Outcome Measures: Insulin sensitivity (SI), acute insulin response to iv glucose (AIRg), and disposition index (AIRg × SI, or β-cel...

Journal of Biopharmaceutical Statistics, 2004

We describe some theory and recent enhancements for the SAS macro NLINMIX (Wolfinger, R. D. (1993... more We describe some theory and recent enhancements for the SAS macro NLINMIX (Wolfinger, R. D. (1993). Laplace&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s approximation for nonlinear mixed effects models. Biometrika 80:791-795) that enable model calculation to take place within the interaction matrix language SAS/IML (SAS Institute Inc. (1999a). SAS/IML User&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s Guide Version 7. Cary, NC: SAS Institute Inc.). They provide greater flexibility and scope for the specification and analysis of complex nonlinear mixed models. For example, using data from a frequently sampled intravenous glucose test, we fit a two-compartment kinetics model that has no closed-form representation. It is derived as the solution of a system of ordinary differential equations and specified as such in SAS/IML. Additional details and example NLINMIX code are available in Appendix A.

Diabetes, 2003

Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion in a glucose-dependent manner, but i... more Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion in a glucose-dependent manner, but its short half-life limits its therapeutic potential. We tested NN2211, a long-acting GLP-1 derivative, in 10 subjects with type 2 diabetes (means ± SD: age 63 ± 8 years, BMI 30.1 ± 4.2 kg/m2, HbA1c 6.5 ± 0.8%) in a randomized, double-blind, placebo-controlled, crossover study. A single injection (7.5 μg/kg) of NN2211 or placebo was administered 9 h before the study. β-cell sensitivity was assessed by a graded glucose infusion protocol, with glucose levels matched over the 5–12 mmol/l range. Insulin secretion rates (ISRs) were estimated by deconvolution of C-peptide levels. Findings were compared with those in 10 nondiabetic volunteers during the same glucose infusion protocol. In type 2 diabetic subjects, NN2211, in comparison with placebo, increased insulin and C-peptide levels, the ISR area under the curve (AUC) (1,130 ± 150 vs. 668 ± 106 pmol/kg; P < 0.001), and the slope of ISR ve...

Diabetes, 1991

The purposes of this study were to determine whether patients with non-insulin-dependent diabetes... more The purposes of this study were to determine whether patients with non-insulin-dependent diabetes mellitus (NIDDM) have an enhanced glycemic response to epinephrine (EPI) and to quantitate the effect of physiological elevations of EPI on pancreatic islet function in these patients. The increment of plasma glucose (PG) in response to 45 min of EPI infusion (mean plasma EPI 2490 pM) was more than twofold greater in nine NIDDM patients than in 20 nondiabetic control subjects (mean +/- SE delta PG 3.9 +/- 0.3 vs. 1.7 +/- 0.1 mM, P less than 0.0001). The effects of EPI on beta-cell and alpha-cell function were compared in nine NIDDM patients and 9 age- and weight-matched control subjects during infusions of saline or two doses of EPI on separate days (mean plasma EPI 270, 1120, and 2490 pM). On each day, the acute insulin response (AIR) and acute glucagon response (AGR) to 5 g i.v. arginine were measured at three matched steady-state PG levels (means of 9, 14, and 29 mM). Beta-Cell sensitivity to glucose (slope of glucose potentiation) and beta-cell secretory capacity, or AIRmax (AIR at the highest clamped PG level), were calculated. In control subjects, EPI inhibited the AIR at PG concentrations of 9 and 14 mM (both P less than 0.05) but had no effect on the AIRmax, resulting in a rightward shift of the curve relating the AIR and PG and a decrease in the slope of glucose potentiation (P less than 0.01). In contrast in NIDDM patients, EPI inhibited the AIR at all PG levels, including the AIRmax (all P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetes, 1994

Maturity-onset diabetes of the young (MODY) is a form of non-insulin-dependent diabetes mellitus ... more Maturity-onset diabetes of the young (MODY) is a form of non-insulin-dependent diabetes mellitus (NIDDM) associated with autosomal-dominant inheritance. In the RW pedigree, MODY is associated with polymorphic DNA markers on chromosome 20q. To determine the early abnormalities of insulin action and insulin secretion in MODY, we studied nondiabetic members of the RW pedigree with and without the gene marker. Six nondiabetic marker-negative and 5 nondiabetic marker-positive members of the RW pedigree were studied, as were 4 diabetic marker-positive family members. Unrelated, young, healthy subjects served as comparison groups. Insulin action and insulin secretion were assessed with a frequently sampled intravenous glucose tolerance test. Insulin secretion was further assessed during constant glucose infusion by deconvolution of plasma C-peptide and by pulse analysis. The nondiabetic marker-positive group had normal sensitivity to insulin and unimpaired acute insulin response to intravenous glucose (AIR_ lu). However, the nondiabetic marker-positive group had decreased mean plasma C-peptide concentration and reduced absolute amplitude of insulin secretory oscillations during prolonged glucose infusion. These responses to

Diabetes, 1997

Nondiabetic subjects with the Q268X mutation in the hepatocyte nuclear factor (HNF)-4α/MODY1 gene... more Nondiabetic subjects with the Q268X mutation in the hepatocyte nuclear factor (HNF)-4α/MODY1 gene have impaired glucose-induced insulin secretion. To ascertain the effects of the nonglucose secretagogue arginine on insulin and glucagon secretion in these subjects, we studied 18 members of the RW pedigree: 7 nondiabetic mutation negative (ND[−]), 7 nondiabetic mutation positive (ND[+]), and 4 diabetic mutation positive (D[+]). We gave arginine as a 5-g bolus, followed by a 25-min infusion at basal glucose concentrations, and after glucose infusion to clamp plasma glucose at ∼200 mg/dl. The acute insulin response (AIR), the 10–60 min insulin area under the curve (AUC), and the insulin secretion rate (ISR) were compared, as were the acute glucagon response (AGR) and glucagon AUC. The ND[+] and D[+] groups had decreased insulin AUC and ISR and decreased glucose potentiation of AIR, insulin AUC, and ISR to arginine administration when compared with the ND[−] group. At basal glucose concentrations, glucagon AUC was greatest for the ND[−] group, intermediate for the ND[+] group, and lowest for the D[+] group. During the hyperglycemic clamp, there was decreased suppression of glucagon AUC for both ND[+] and D[+] groups compared with the ND[−] group. The decreased ISR to arginine in the ND[+] group compared with the ND[−] group, magnified by glucose potentiation, indicated that HNF-4α affects the signaling pathway for arginine-induced insulin secretion. The decrease in glucagon AUC and decreased suppression of glucagon AUC with hyperglycemia suggest that mutations in HNF-4α may lead to α-cell as well as β-cell secretory defects or a reduction in pancreatic islet mass.

American Journal of …, 1989

American Journal of …, 1991

American Journal of …, 1990

Journal of the American Geriatrics Society, 1997

The American journal of physiology, 1994

The American journal of physiology, 1989

The Journal of pharmacology and experimental therapeutics, 1990

The American journal of physiology, 1990

The American journal of physiology, 1991

The American journal of physiology, 1990

Metabolism, 1991

Journal of Clinical Investigation, 1987

The Journal of Clinical Hypertension, 2010

The Journal of Clinical Endocrinology & Metabolism, 2006

Journal of Biopharmaceutical Statistics, 2004

Diabetes, 2003

Diabetes, 1991

Diabetes, 1994

Diabetes, 1997

American Journal of …, 1989

American Journal of …, 1991

American Journal of …, 1990