Dietary patterns, beliefs and behaviours among individuals with inflammatory bowel disease: a cross-sectional study.

BACKGROUND: Inflammatory bowel disease (IBD) refers to a group of incurable gastrointestinal diseases that are common among young adults. The present study aimed to describe dietary intake, self-modifications and beliefs among adults aged 18-35 years with IBD and to compare those with active versus inactive disease. National guidelines for daily intake include: 34 g of fibre for males and 28 g of fibre for females, 3 oz of whole grains, 1000 mg of calcium, <10% of added sugars, three cups of dairy, 2.5 cups of vegetables and two cups of fruit. METHODS: Individuals with a diagnosis of IBD were recruited online using convenience sampling (n = 147). Data included a dietary screening questionnaire, self-directed diet modifications, dietary beliefs questionnaire and demographics. Chi-squared and t-tests were used to compare those with active versus inactive disease. RESULTS: The sample was predominantly female (90%) and diagnosed with Crohn's disease (64%). Daily intake for females was 9.7 g of fibre, 0.3 oz of whole grains, 683.8 g of calcium, 1.1 of cups vegetables and 0.5 of cups fruit. Daily intake for males was 14.2 g of fibre, 0.4 oz of whole grains, 882.9 g of calcium, 1.4 cups of vegetables and 0.5 cups of fruit. Participants most often modified fibre (73%), fruits and vegetables (71%), grains (67%), and dairy (66%) as a result of their IBD. Eighty-three percent believed that modifying their diet could reduce IBD symptoms. CONCLUSIONS: Both men and women with IBD struggle to meet the national guidelines for intake of fibre, whole grains, fruits and vegetables. The majority reported modifying their dietary intake as a result of IBD and expressed belief that diet could reduce symptoms.

Barriers to mental health service use among distressed family caregivers of lung cancer patients.

Although family caregivers of patients with lung and other cancers show high rates of psychological distress, they underuse mental health services. This qualitative study aimed to identify barriers to mental health service use among 21 distressed family caregivers of lung cancer patients. Caregivers had not received mental health services during the patient's initial months of care at a comprehensive cancer centre in New York City. Thematic analysis of interview data was framed by Andersen's model of health service use and Corrigan's stigma theory. Results of our analysis expand Andersen's model by providing a description of need variables (e.g. psychiatric symptoms), enabling factors (e.g. finances), and psychosocial factors associated with caregivers' non-use of mental health services. Regarding psychosocial factors, caregivers expressed negative perceptions of mental health professionals and a desire for independent management of emotional concerns. Additionally, caregivers perceived a conflict between mental health service use and the caregiving role (e.g. prioritising the patient's needs). Although caregivers denied stigma associated with service use, their anticipated negative self-perceptions if they were to use services suggest that stigma may have influenced their decision to not seek services. Findings suggest that interventions to improve caregivers' uptake of mental health services should address perceived barriers.

Quality of life among patients with primary, metastatic and recurrent cancer.

Diagnosis of cancer is an emotionally traumatic event that significantly impacts the quality of life (QoL) of the patients. Progression to metastasis or recurrence of cancer after first diagnosis poses a greater threat to life that further increases this emotional trauma and can worsen the QoL. In this research we sought to explore the differences in QoL (symptom severity and physical functioning) experienced by primary non-metastatic (PNM), primary metastatic (PM) and recurrent (RC) cancer patients. Cancer patients recruited in two cognitive intervention trials formed the sample for this analysis. Data were analysed using longitudinal mixed models, with two interaction terms. Least square means were calculated and compared. Over the period of study RC patients reported the worst symptom severity and physical function followed by PM and PNM patients. Primary non-metastatic patients showed a steady decline in severity whereas PM and RC showed slight gains after the first follow-up. Primary non-metastatic patients displayed best physical functioning followed by PM and RC patients, and remained stable over time. Breast cancer patients displayed most variation in symptom severity among the three progression groups, whereas significant variation in physical function among the three groups was observed within all cancer sites.

Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects.

The pattern of endogenous insulin secretion over a 24-h period, which included three mixed meals, was evaluated in 14 normal volunteers and 15 obese subjects. Insulin secretory rates were calculated from plasma C-peptide levels using individually derived C-peptide kinetic parameters and a validated open two-compartment model of peripheral C-peptide kinetics. Insulin secretion rates were consistently elevated in the obese subjects under basal conditions (11.6 +/- 1.2 vs. 5.4 +/- 0.5 nmol/h) and in the 4 h after breakfast (139 +/- 15 vs. 63 +/- 5 nmol/4 h, P less than 0.001), lunch (152 +/- 16 vs. 67 +/- 5 nmol/4 h, P less than 0.001), and dinner (145 +/- 18 vs. 65 +/- 6 nmol/4 h, P less than 0.001). In the normal subjects, basal insulin secretion represented 50 +/- 2.1% of total 24-h insulin production, insulin secretion returned to baseline between meals, and equal quantities of insulin were secreted in the 4 h after breakfast, lunch, and dinner, despite the fact that subjects consumed half the number of calories at breakfast compared to lunch and dinner. Overall glucose responses were also similar after the three meals. In contrast, the pattern of insulin secretion in obese subjects was largely normal, albeit set at a higher level. However, the insulin secretion rate after meals did not return to baseline, and the secretion rate immediately before lunch (350.5 +/- 81.9 pmol/min) and dinner (373.6 +/- 64.8 pmol/min) was considerably higher than the secretion rate immediately before breakfast (175.5 +/- 18.5 pmol/min). In these overweight subjects, the glucose response after lunch was lower than after dinner. Analysis of individual 24-h insulin secretory profiles in the normal subjects revealed that insulin secretion was pulsatile. On average 11.1 +/- 0.5 pulses were produced in each 24-h period. The most prevalent temporal distribution of postmeal secretory pulses was two pulses after breakfast and three pulses after both lunch and dinner. Insulin secretion was also pulsatile during the period without meal stimuli: 3.9 +/- 0.3 pulses occurred during the period of overnight sampling and in the 3-h period before ingestion of the breakfast meal. In the obese subjects, the number and timing of secretory pulses was similar to those of normal volunteers, although the amplitude of the pulses was significantly greater. In both groups of subjects, greater than 80% of insulin pulses were concomitant with a pulse in glucose concentration in the postmeal period. The concomitancy rate was significantly lower in the interval without the meal stimuli, averaging 47% in both groups. Thus in obesity, although hypersecretion of insulin can be documented, the temporal pattern of secretion i s largely unaltered, which suggests that the functioning beta cell mass is enhance, but normal regulatory mechanisms influencing secretion are still operative.

Biochemical and clinical implications of proinsulin conversion intermediates.

Since a complete map of insulin-related peptides in humans requires consideration of proinsulin, Arg32/Glu33-split proinsulin, Arg65/Gly66-split proinsulin, des-Arg31,Arg32-proinsulin, des-Lys64, Arg65-proinsulin, and insulin, we applied high performance liquid chromatography coupled with radioimmunoassay to investigate the formation of proinsulin conversion intermediates in vitro and in vivo. Kinetic analysis of proinsulin processing by a mixture of trypsin and carboxypeptidase B (to stimulate in vivo processes) revealed (a) a rapid decline in proinsulin concommitant with formation of conversion intermediates, (b) formation of des-Arg31, Arg32-proinsulin and des-Lys64,Arg65-proinsulin in the ratio 3.3:1 at steady state, and (c) complete conversion of the precursor to insulin during extended incubation. Studies on normal human pancreas identified a similar ratio of des-Arg31,Arg32-proinsulin to des-Lys64,Arg65-proinsulin (approximately 3:1), whereas two insulinomas contained sizable amounts of des-Arg31,Arg32-proinsulin, but barely detectable amounts of des-Lys64,Arg65-proinsulin. None of the tissues contained measurable quantities of Arg32/Glu33- or Arg65/Gly66-split proinsulin. Analysis of plasma from three diabetic subjects managed by the intravenous infusion of human proinsulin revealed less than 1% processing of the circulating precursor to conversion intermediates and no processing of the precursor to human insulin. Nevertheless, analysis of plasma from the same subjects managed by the subcutaneous infusion of proinsulin revealed 4-11% processing of the precursor to intermediates that had the properties of des-Arg31,Arg32-proinsulin and Arg65/Gly66-split proinsulin. We conclude that (a) processing of proinsulin to insulin in vivo as in vitro likely occurs by preferential cleavage at the Arg32-Glu33 peptide bond in proinsulin, (b) proinsulin is inefficiently processed in the vascular compartment, and (c) subcutaneous administration of the precursor can result in the formation of conversion intermediates with the potential for contributing to biological activity.

Use of biosynthetic human C-peptide in the measurement of insulin secretion rates in normal volunteers and type I diabetic patients.

We undertook this study to examine the accuracy of plasma C-peptide as a marker of insulin secretion. The peripheral kinetics of biosynthetic human C-peptide (BHCP) were studied in 10 normal volunteers and 7 insulin-dependent diabetic patients. Each subject received intravenous bolus injections of BHCP as well as constant and variable rate infusions. After intravenous bolus injections the metabolic clearance rate of BHCP (3.8 +/- 0.1 ml/kg per min, mean +/- SEM) was not significantly different from the value obtained during its constant intravenous infusion (3.9 +/- 0.1 ml/kg per min). The metabolic clearance rate of C-peptide measured during steady state intravenous infusions was constant over a wide concentration range. During experiments in which BHCP was infused at a variable rate, the peripheral concentration of C-peptide did not change in proportion to the infusion rate. Thus, the infusion rate of BHCP could not be calculated accurately as the product of the C-peptide concentration and metabolic clearance rate. However, the non-steady infusion rate of BHCP could be accurately calculated from peripheral C-peptide concentrations using a two-compartment mathematical model when model parameters were derived from the C-peptide decay curve in each subject. Application of this model to predict constant infusions of C-peptide from peripheral C-peptide concentrations resulted in model generated estimates of the C-peptide infusion rate that were 101.5 +/- 3.4% and 100.4 +/- 2.8% of low and high dose rates, respectively. Estimates of the total quantity of C-peptide infused at a variable rate over 240 min based on the two-compartment model represented 104.6 +/- 2.4% of the amount actually infused. Application of this approach to clinical studies will allow the secretion rate of insulin to be estimated with considerable accuracy. The insulin secretion rate in normal subjects after an overnight fast was 89.1 pmol/min, which corresponds with a basal 24-h secretion of 18.6 U.

Diabetes due to secretion of a structurally abnormal insulin (insulin Wakayama). Clinical and functional characteristics of [LeuA3] insulin.

We have identified a non-insulin-dependent diabetic patient with fasting hyperinsulinemia (90 microU/ml), an elevated insulin:C-peptide molar ratio (1.68; normal, 0.05-0.20), normal insulin counterregulatory hormone levels, and an adequate response to exogenously administered insulin. Insulin-binding antibodies were absent from serum, erythrocyte insulin receptor binding was normal, and greater than 90% of circulating immunoreactive insulin coeluted with 125I-labeled insulin on gel filtration. The patient's insulin diluted in parallel with a human standard in the insulin radioimmunoassay, confirming close molecular similarity. The patient's insulin was purified from serum and shown to possess both reduced binding and ability to stimulate glucose uptake and oxidation in vitro. Analysis of the patient's insulin by high-performance liquid chromatography (HPLC) revealed two products: 7.3% of insulin immunoreactivity coeluted with the human standard, while the remaining 92.7% eluted as a single peak with increased hydrophobicity. Family studies confirmed the presence of hyperinsulinemia in four of five relatives in three generations, with secretion of an abnormal insulin documented by HPLC in the three tested. Leukocyte DNA was harvested from the propositus and the insulin gene cloned. One allele was normal, but the other displayed a thymine for guanine substitution at nucleotide position 1298 from the putative cap site, resulting in a leucine for valine substitution at position 3 of the insulin A chain. Insulin Wakayama is therefore identified as [LeuA3] insulin.

Quantitative study of insulin secretion and clearance in normal and obese subjects.

The secretion and hepatic extraction of insulin were compared in 14 normal volunteers and 15 obese subjects using a previously validated mathematical model of insulin secretion and rate constants for C-peptide derived from analysis of individual decay curves after intravenous bolus injections of biosynthetic human C-peptide. Insulin secretion rates were substantially higher than normal in the obese subjects after an overnight fast (86.7 +/- 7.1 vs. 50.9 +/- 4.8 pmol/m2 per min, P less than 0.001, mean +/- SEM), over a 24-h period on a mixed diet (279.6 +/- 24.2 vs. 145.8 +/- 8.8 nmol/m2 per 24 h, P less than 0.001), and during a hyperglycemic intravenous glucose infusion (102.2 +/- 10.8 vs. 57.2 +/- 2.8 nmol/m2 per 180 min, P less than 0.001). Linear regression analysis revealed a highly significant relationship between insulin secretion and body mass index. Basal hepatic insulin extraction was not significantly different in the normal and obese subjects (53.1 +/- 3.8 vs. 51.6 +/- 4.0%). In the normal subjects, fasting insulin did not correlate with basal hepatic insulin extraction, but a significant negative correlation between fasting insulin and hepatic insulin extraction was seen in obesity (r = -0.63, P less than 0.02). This finding reflected a higher extraction in the six obese subjects with fasting insulin levels within the range of the normal subjects than in the nine subjects with elevated fasting insulin concentrations (61 +/- 3 vs. 45 +/- 6%, P less than 0.05). During the hyperglycemic clamp, the insulin secretion rate increased to an average maximum of 6.2-fold over baseline in the normal subjects and 5.8-fold in the obese subjects. Over the same time, the peripheral insulin concentration increased 14.1-fold over baseline in the normals and 16.6-fold over baseline in the obese, indicating a reduction in the clearance of endogenously secreted insulin. Although the fall in insulin clearance tended to be greater in the obese subjects, the differences between the two groups were not statistically significant. Thus, under basal, fasting conditions and during ingestion of a mixed diet, the hyperinsulinemia of obesity results predominantly from increased insulin secretion. In patients with more marked basal hyperinsulinemia and during intense stimulation of insulin secretion, a reduction in insulin clearance may contribute to the greater increase in peripheral insulin concentrations that are characteristic of the obese state.+

Discordance between patient and clinician reports of adverse reactions to MDR-TB treatment.

SETTING: An urban out-patient clinic in Durban, South Africa, providing community-based treatment for drug-resistant tuberculosis (TB). OBJECTIVE: To describe concordance between patient report and clinician documentation of adverse drug reactions (ADRs) to treatment for multidrug-resistant TB (MDR-TB). DESIGN: ADRs were documented by interview using an 18-item symptom checklist and medical record data abstraction during a cross-sectional parent study with 121 MDR-TB patients, 75% of whom were co-infected with the human immunodeficiency virus. Concordance was analyzed using Cohen's κ statistic, Gwet's agreement coefficient (AC) 1, and McNemar's test. RESULTS: ADRs were reported much more frequently in patient interviews (µ = 8.6) than in medical records (µ = 1.4). Insomnia was most common (67% vs. 2%), followed by peripheral neuropathy (65% vs. 18%), and confusion (61 vs. 4%). κ scores were very low, with the highest degree of concordance found in hearing loss (κ = 0.23), which was the only ADR not found to be significantly different between the two data sources (P = 0.34). CONCLUSIONS: Our study showed a lack of concordance between patient report and clinician documentation of ADRs. These findings indicate the need for improved documentation of ADRs to better reflect patients' experiences during MDR-TB treatment. These data have important implications for country-level pharmacovigilance programs that rely on clinician documentation of ADRs for MDR-TB policy formation.

Pursuing Quality in the Application of Bladder Cancer Quality of Life Research.

Patient-reported outcomes (PRO), including health-related quality of life (HRQOL) measures, represent important means for evaluating patients' health outcomes and for guiding health care decisions made by patients, practitioners, investigators, and policy makers. In spite of the large number of studies examining HRQOL in patients with bladder cancer, very few review articles investigated this topic. Because these review studies report mixed results, incorporating bladder cancer HRQOL measures into standard urological practice is not a viable option. In this non-systematic review of the literature and commentary we note some general concerns regarding PRO research, but our primary focus is on the HRQOL methodology within the context of two types of bladder cancer: muscle invasive and non-muscle invasive bladder cancer. Considering bladder cancer HRQOL as the interaction of four areas of the assessment process (i.e., what model of HRQOL to choose, what instruments are available to fit the choice, how interpretation of the resulting data fits the model, and how to derive some utility from the chosen model) and the two types of disease (i.e., muscle invasive and non-muscle invasive) may move us toward a better understanding of bladder cancer HRQOL. Establishing a useful model of perceived general health or specific symptoms is the first and most important step in developing the responsive bladder cancer HRQOL measures necessitated by clinical settings.

Change in hexose distribution volume and fractional utilization of [18F]-2-deoxy-2-fluoro-D-glucose in brain during acute hypoglycemia in humans.

We used positron emission tomography (PET) to study the effects of mild hypoglycemia on cerebral glucose uptake and metabolism. Nine healthy men were studied under basal saline-infusion conditions, and during euglycemic and hypoglycemic clamp studies. Insulin was infused at the same rate (1 mU.kg-1.min-1) in both clamp studies. In euglycemic clamp studies, glucose was infused at a rate sufficient to maintain the basal plasma glucose concentration, whereas in hypoglycemic clamp studies, the glucose infusion rate was reduced to maintain the plasma glucose at 3.1 mM. Each study lasted 3 h and included a 30-min baseline period and a subsequent 150-min period in which insulin or glucose was administered. Blood samples for measurement of insulin, glucose, cortisol, growth hormone, and glucagon were obtained at 20- to 30-min intervals. A bolus injection of 5-10 mCi [18F]-2-deoxy-2-fluoro-D-glucose (2-DFG) was administered 120 min after initiation of the study, and plasma radioactivity and dynamic PET scans were obtained at frequent intervals for the remaining 40-60 min of the study. Cerebral regions of interest were defined, and concentrations of radioactivity were calculated and used in the three-compartment model of 2-DFG distribution described by Sokoloff. Glucose levels were similar during saline-infusion (4.9 +/- 0.1 mM) and euglycemic clamp (4.8 +/- 0.1 mM) studies, whereas the desired degree of mild hypoglycemia was achieved during the hypoglycemic clamp study (3.1 +/- 0.1 mM, P less than 0.05). The insulin level during saline infusion was 41 +/- 7 pM.(ABSTRACT TRUNCATED AT 250 WORDS)

Reevaluation of urine C-peptide as measure of insulin secretion.

Urine C-peptide (UCP) has been proposed as a measure of insulin secretion, because insulin and C-peptide are consecreted in equimolar concentrations by the pancreatic beta-cell. The validity of this approach was tested by comparing insulin secretion rates, calculated by application of a two-compartmental analysis of peripheral C-peptide concentrations, with UCP excretion rates. Insulin secretion and UCP excretion with subjects on a mixed diet were simultaneously measured over a 24-h period in 13 patients with noninsulin-dependent diabetes mellitus and in 14 matched nondiabetic control subjects. The fraction of secreted C-peptide that was excreted in the urine (fractional C-peptide excretion) showed considerable intersubject variability in the diabetic (11.3 +/- 1.6%, range 3.9-20.8) and control (8.0 +/- 1.7%, range 1.1-27.9, P = .07) subjects (means +/- SE). UCP clearance demonstrated a similar degree of variability and was not significantly different (P = .07) between diabetic (23.8 +/- 3.0 ml/min) and control (16.5 +/- 2.7 ml/min) subjects. In control subjects, the 24-h insulin secretion rate correlated more closely with the fasting insulin secretion rate (r = .97, P = .0001), fasting C-peptide (r = .81, P = .0005), and fasting insulin (r = .80, P = .0005) concentrations than with the 24-h UCP excretion rate (r = .62, P = .02). Similar results were obtained in the diabetic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Symptomatic hypotension following the clonidine suppression test for pheochromocytoma.

A 42-year-old man with generalized atherosclerosis underwent surgery of the left carotid artery with eventual placement of a Dacron graft bypassing the left carotid sinus. Subsequently, symptoms suggestive of pheochromocytoma developed, and 24-hour urine catecholamine levels were elevated. Clonidine testing resulted in suppression of plasma norepinephrine levels but was complicated by severe hypotension and a transient ischemic attack. Baroreceptor dysfunction may have been involved. Caution is advised and recommendations are offered for future usage of the clonidine suppression test.

Nifedipine in severely hypertensive patients with congestive heart failure and preserved ventricular systolic function.

Nifedipine was used successfully in nine patients with refractory hypertension and left ventricular hypertrophy who had symptoms of congestive heart failure despite preserved left ventricular systolic function. The administration of 10 or 20 mg of nifedipine resulted in an acute decline in BP, from 211 +/- 8/105 +/- 6 mm Hg to 153 +/- 9/78 +/- 5 mm Hg. Six patients received nifedipine and one patient received long-term verapamil therapy (mean follow-up, 16 +/- 4 weeks). In addition to sustained BP control, signs and symptoms of congestive heart failure were greatly improved in all patients treated long term with calcium channel antagonists. No adverse reactions were reported, but a short duration of action limited their usefulness in some patients. Nifedipine seems to be particularly beneficial in this subgroup of severe hypertensive patients with heart failure presumably due to diastolic stiffness of the left ventricle.

Hypoglycemia due to surreptitious injection of insulin. Identification of insulin species by high-performance liquid chromatography.

OBJECTIVE: To identify the circulating species of insulin after separation by high-performance liquid chromatography (HPLC) in patients with factitious hypoglycemia. RESEARCH DESIGN AND METHODS: In three of four patients presented, the diagnosis of surreptitious insulin injection was made by documenting the presence of animal insulin in the circulation after separation of the circulating insulin forms by HPLC. RESULTS: Animal insulin was identified. CONCLUSIONS: Thus, the identification of the circulating form of insulin in the circulation by HPLC may be a useful adjunct in the diagnosis of factitious hypoglycemia if animal insulin has been injected and if the simultaneously measured concentrations of insulin and C-peptide are inconclusive.

Ingestion of a mixed meal does not affect the metabolic clearance rate of biosynthetic human C-peptide.

The validity of C-peptide as a peripheral marker of insulin secretion during different physiological conditions depends on the demonstration that C-peptide clearance is constant under these circumstances. Recently biosynthetic human C-peptide, identical in structure to pancreatic human C-peptide, became available for use in human subjects. The present study was undertaken to determine if the metabolic clearance of C-peptide was altered by ingestion of a mixed meal. Eight insulin-dependent diabetic patients received constant iv infusions of biosynthetic human C-peptide which raised the plasma C-peptide concentration to a level of 3.8 +/- 0.2 (+/- SEM) pmol/ml. The MCR of C-peptide was 4.5 +/- 0.3 ml/kg X min. After steady state levels of C-peptide had been reached, each patient consumed a 530 calorie mixed meal. The plasma glucose concentration increased from a baseline value of 104.5 +/- 4.8 mg/dl to a 336 +/- 10 mg/dl 150 min later. This change in plasma glucose was not associated with a significant alteration in the plasma C-peptide concentration and the MCR of the infused C-peptide was not affected by meal ingestion (4.5 +/- 0.3 vs. 4.3 +/- 0.3 ml/kg X min). These results therefore support the validity of using C-peptide as a marker for changes in insulin secretion after mixed meals.

Prostaglandin E2 analogue elicits renal and hormonal compensatory mechanisms in human hypertension.

Endogenous prostaglandin E2 appears to play an important role in cardiovascular homeostasis. When administered exogenously, it is a potent vasodilator, but the requirement for intravenous administration and its short duration of action have limited studies to its acute effects. A novel prostaglandin E2 analogue, CL 115347, can be administered transdermally on a long-term basis. The cardiovascular responses to the chronic administration of CL 115347 were studied in a double-blind, placebo-controlled trial in 26 subjects with essential hypertension (16 given drug, 10 placebo) maintained on a 100-mEq sodium diet. Administration of CL 115347 produced a fall in diastolic blood pressure of 7.8 +/- 1.3 mm Hg, compared with a 2.3 +/- 1.7 mm Hg fall in controls (p = 0.02), with no change in heart rate. The direct vascular effect of the drug was confirmed by attenuation of the vasoconstrictor response to angiotensin II infusion (13.4 +/- 3.1 vs 21 +/- 2 mm Hg at 3.0 ng/kg/min; p less than 0.05). However, the chronic blood pressure effect of CL 115347 was modest. Subjects receiving active drug showed significant compensatory increases in plasma renin, aldosterone, and norepinephrine levels accompanied by sodium retention and kaliuresis. In summary, chronic administration of this prostaglandin E2 analogue resulted in a modest decrease in blood pressure and antagonism of angiotensin II-mediated vasoconstriction. However, its effects were largely offset by compensatory increases in vasoconstrictor hormones and sodium retention.

Calculation of the systemic delivery rate of insulin in normal man.

The accuracy with which the systemic delivery rate of insulin can be estimated from peripheral insulin concentrations was investigated in eight normal men. Endogenous insulin secretion was suppressed by somatostatin, and insulin was infused exogenously via a peripheral vein. The infusion rate was progressively increased and then decreased to stimulate the changes in insulin secretion that occur after a secretory stimulus. The infusion rate of insulin was then estimated by analyzing peripheral insulin concentrations using both single and two-compartment mathematical models and was compared with the actual infusion rates. Model parameters were measured in each subject by analysis of the insulin decay curve after a bolus injection. Estimated infusion rates based on the single compartment model were 84.3 +/- 3.0% (mean +/- SE) of the actual infusion rate as it was increasing and 110.3 +/- 3.7% of the infusion rate as it was decreasing. The mean overall absolute percent error associated with this approach was 14.1 +/- 1.0% (range, 10.2-18.8%), and model estimates of the total amount of insulin infused over the duration of the experiment were 97.1 +/- 3.2% of the quantity actually infused (range, 85.4-110.7%). Estimates of the infusion rate based on a two-compartment model represented 90.3 +/- 3.1% of the actual infusion rate as it was increasing and 98.2 +/- 3.2% of the actual rate as it was falling. The area under the derived infusion rate curve was 94.8 +/- 2.8% of the area under the actual curve. The overall error associated with the use of the two-compartment model was 12.9 +/- 1.1% (range, 8.8-18.6%). Differences between the single and two-compartment models were minor and not statistically significant. These data demonstrate that under euglycemic conditions, changes in the plasma insulin concentration within the physiological range are not associated with changes in the clearance kinetic rate constants of the hormone. Furthermore, the systemic delivery rate of insulin can be accurately derived from peripheral insulin concentrations using either a single or two-compartmental model if model parameters are accurately measured in individual subjects by analysis of insulin decay curves.

Glyburide enhances the responsiveness of the beta-cell to glucose but does not correct the abnormal patterns of insulin secretion in noninsulin-dependent diabetes mellitus.

Eleven patients with noninsulin-dependent diabetes mellitus were studied before and after 6-10 weeks of glyburide therapy. Patients were studied during a 24-h period on a mixed diet comprising 30 Cal/kg divided into three meals. The following day a hyperglycemic clamp study was performed, with glucose levels clamped at 300 mg/dL (16.7 mmol/L) for a 3-h period. Insulin secretion rates were calculated by deconvolution of peripheral C-peptide concentrations using individual C-peptide clearance kinetics derived after bolus injection of biosynthetic human C-peptide. After 6-10 weeks on glyburide, the identical studies were repeated. In response to glyburide, the fasting plasma glucose level decreased from 12.3 +/- 1.2 to 6.8 +/- 0.9 mmol/L. Although the mean glucose over the 24 h of the meal study decreased from 12.7 +/- 1.4 to 10.8 +/- 1.2 mmol/L, postprandial hyperglycemia persisted on therapy, and after breakfast, glucose levels exceeded 10 mmol/L and did not return to fasting levels for the remainder of the day. Fasting serum insulin, plasma C-peptide, and the insulin secretion rate were not different before (152 +/- 48 pmol/L, 0.82 +/- 0.16 pmol/mL, and 196 +/- 34 pmol/min, respectively) and after (186 +/- 28 pmol/L, 0.91 +/- 0.11 pmol/mL, and 216 +/- 23 pmol/min, respectively) glyburide treatment despite lowering of the glucose level. However, average insulin and C-peptide concentrations over the 24-h period increased from 366 +/- 97 pmol/L and 1.35 +/- 0.19 pmol/mL to 434 +/- 76 pmol/L and 1.65 +/- 0.15 pmol/mL, respectively. The total amount of insulin secreted over the 24-h period rose from 447 +/- 58 nmol before therapy to 561 +/- 55 nmol while receiving glyburide. Insulin secretion was demonstrated to be pulsatile in all subjects, with periodicity ranging from 2-2.5 h. The number of insulin secretory pulses was not altered by glyburide, whereas pulse amplitude was enhanced after lunch and dinner, suggesting that the increased insulin secretion is characterized by increased amplitude of the individual pulses. In response to a hyperglycemic clamp at 300 mg/dL (16.7 mmol/L), insulin secretion rose more than 2-fold, from 47 +/- 9 nmol over the 3-h period before treatment to 103 +/- 21 nmol after glyburide therapy. We conclude that the predominant mechanism of action of glyburide in patients receiving therapy for 6-10 weeks is to increase the responsiveness of the beta-cell to glucose.(ABSTRACT TRUNCATED AT 400 WORDS)

Pharmacokinetics and pharmacodynamics of dilevalol.

The pharmacokinetics and pharmacodynamics of dilevalol, the R,R stereoisomer of labetalol, were evaluated in nine subjects. Dilevalol was given as a single 50 mg intravenous dose and as a 400 mg daily oral dose for 7 days. To study the effects of hepatic enzyme inhibition, each subject received dilevalol in the presence of and absence of cimetidine. Cardiac beta-blockade was assessed by use of standardized treadmill tests for 48 hours after oral dilevalol. The three-compartment model analysis showed that systemic clearance (29.8 +/- 5.7 ml/min/kg), volume of distribution (16.6 +/- 4.1 L/kg), and terminal half-life (11.7 +/- 2.7 hours) were not altered by cimetidine. However, there was a 20% increase in the area under the curve (p less than 0.05) and an 11% increase in systemic bioavailability (p less than 0.05) after oral administration. Dilevalol caused significant cardiac beta-blockade for more than 24 hours, but these effects were not altered by cimetidine. The pharmacokinetic changes are consistent with a decrease in first-pass extraction of a high clearance drug.