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OBJECTIVE: The aim of the present study was to evaluate the impact of hypothyroidism on the autonomic regulation of the cardiovascular system by analysing separately sympathetic and parasympathetic influences on the heart. DESIGN: In seven newly diagnosed untreated hypothyroid patients we analysed power spectral density of heart rate cyclic variations at rest, while lying, and while standing. The same protocol was repeated after the induction of stable euthyroidism by levothyroxine (L-T(4)) treatment. The results were also compared with those obtained from seven age-, sex- and body mass index-matched control subjects. METHODS: Heart rate variability was evaluated by autoregressive power spectral analysis (PSA). This method allows reliable quantification of low frequency (LF) and high frequency (HF) components of the heart rate power spectral density. These are considered to be under mainly sympathetic and purely parasympathetic control respectively. In addition, heart rate variations during deep breathing, lying to standing, and Valsalva's manoeuvre were assessed. RESULTS: PSA showed a sharp reduction in the HF (parasympathetic) component in hypothyroid subjects compared with controls (lying, 29.4+/-5.4 vs 47.7+/-6.3 normalized units (NU) (means +/- s.e.m.), P<0.05; standing, 14.0+/-3.5 vs 32.1+/-3.6NU, P<0.005). Conversely, the LF (mainly sympathetic) component was higher in hypothyroid subjects than in controls (lying, 61.6+/-6.4 vs 45.4+/-6.7 NU; standing, 71.7+/-8.0 vs 53.1+/-5.6NU), this difference being significant in the standing position. Hence, the LF/HF ratio, which is considered an index of sympathovagal balance, was increased in hypothyroid subjects while both lying (2.75+/-0.6 vs 1.16+/-0.3; P<0.05) and standing (10.0+/-3.7 vs 1.85+/-0.3; P<0. 02). Total heart rate variability, expressed as total power spectral density, was lower in hypothyroid patients than in control subjects, this difference being significant in the lying position (574+/-126 vs 2302+/-994ms(2), P<0.05). In patients re-examined after L-T(4) therapy, complete normalization of cardiovascular parameters was observed (LF/HF ratio, lying, 1.26+/-0.4; standing, 2.56+/-0.8, both P<0.01 vs baseline values). The response to conventional cardiovascular autonomic tests was not significantly different between hypothyroid patients and healthy controls, and did not change in patients after therapy. CONCLUSIONS: These results suggest that, contrary to the clinical picture, thyroid hormone deficiency is associated with an increased sympathetic influence on the autonomic cardiovascular system. The changes in sympathetic function could be explained by a secondary adaptation to an altered cardiovascular responsiveness.

Poor zinc status is common in cirrhosis. Experimental studies proved that zinc supplementation produces metabolic effects, and trends towards improved liver function and nutritional status have previously been reported. We measured liver function by means of dynamic, quantitative tests and biochemical indices of nutrition in response to zinc treatment in patients with cirrhosis. Fifteen patients with advanced cirrhosis were studied before and after long-term oral zinc-sulfate supplementation (200 mg t.i.d. for 2-3 months). Liver function was measured by routine biochemistry, galactose elimination capacity and antipyrine clearance; nutritional assessment included the measurement of daily urinary creatinine excretion, and albumin, prealbumin, retinol-binding protein and insulin-like growth factor-1 (IGF-1) serum or plasma concentrations. In 10 patients data were correlated with the parameters of glucose metabolism obtained during a frequently-sampled i.v. glucose tolerance test. At baseline, serum zinc was low normal or reduced, and returned to normal range in all patients after supplementation. Liver function improved significantly. All nutritional indices improved as well, but remained on average below normal. IGF-1 increased on average by 30%, but was in the normal range in only 2 cases. Changes in IGF-1 correlated with improved glucose tolerance after i.v. glucose load, namely with the increased non-insulin-mediated glucose uptake. The study confirms that oral zinc produces metabolic effects in zinc-deficient patients with cirrhosis. Improved liver function and nutritional status may increase glucose disposal via increased IGF-1, responsible for the non-insulin-dependent fraction of glucose disappearance.

The refined instrumental variable (RIV) approach to the identification and estimation of multiple input transfer function models has some deficiencies when applied to short time-series obtained from impulse-response-type experiments of the kind used in Diomedical and environmental science. This paper proposes a modifica-tion of the RIV method which corrects these deficiencies by a novel application of the Kalman filter. The practical utility of the method is demonstrated through its application to the analysis of time-series data obtained from experiments on the glucose insulin system in humans and dogs.

The essential role of an integrated identification/validation methodology for developing models of the glucose regulation system is critically discussed. New trends are outlined. Examples are presented on the use of parsimonious, clinically-oriented models and on the use of comprehensive, physiologically-oriented models.

In this paper we apply spectral analysis methods to the heart rate variability signal to assess the autonomic nervous regulation system in both normal subjects ancl patients affected by autonomic neuropathy. Traditional methods for investigating the degree of impairment of the autonomic heart rate regulation system make use of external or self-evoked inputs, which perturb the biological system producing changes in heart rhythm and arterial pressure. Different clinical tests allow to quantify separately sympathetic and parasympathetic activity. The use of power spectral analysis of the heart rate variability signal is an appealing methodology for quantifying the activity of the autonomic nervous system since it can be performed at rest due to the natural “spectral” separation of the sympathetic and parasympathetic control systems. While the first regulatory mechanism acts at the low frequency band of approximately on cycle every ten seconds, the parasympathetic control can act two or three times faster producing rhythmic changes in heart rate of a few seconds. Results show in normal patients a significant reduction of parasympathetic activity in standing position with respect to supine, and in patients affected by severe autonomic neuropathy an overall reduction of power at all frequencies. For autonomic patients there are no significant differences following postural changes. From this study a working hypothesis emerges, concerning pronounced impairment of the sympathetic system as well as the parasympathetic one in autonomic neuropathy, which requires further investigation.

Insulin is suggested to have direct effects on the cardiovascular system but these are not well described. We assessed the possible influence of insulin on autonomic control of heart function. A 2‐h hyperinsulinaemic euglycaemic clamp was performed in 10 healthy women (mean age 21.7 ± 1.3 years), at two different insulin infusion rates: 80 mU m−2and 400 mU m−2min−1, in 7 and 3 subjects, respectively. Saline alone was infused in 4 controls. Power spectral analysis (PSA) of heart rate was recorded before and after 90–120 min of insulin infusion, as were blood pressure and heart rate. Although there were no significant changes in heart rate or blood pressure, PSA showed marked reductions of high frequency (HF) bands after insulin (2.60 ± 0.12 vs 2.09 ± 0.16 log ms2, p< 0.005), as at both low and high infusion rates (2.46 ± 0.13 to 2.14 ± 0.23 log ms2, p< 0.05, and 2.92 ± 0.18 to 1.98 ± 0.06 log ms2, p< 0.01, respectively). There were no significant changes of low frequency (LF) bands. Densities at LF and HF did not change significantly in control studies. As HF and LF are considered to reflect parasympathetic and mainly sympathetic control respectively, our observation of an increased LF/HF ratio (0.13 ± 0.10 vs 0.63 ± 0.13, p< 0.005) may be considered an index of relative sympathetic predominance induced by insulin infusion. We conclude that insulin affects the cardiovascular system, reducing vagal influence on the heart and inducing a relative hypersympathetic tone.

The role of amylin in the β‐cell dysfunction that occurs in patients with diabetes mellitus may be important. Amyloid deposits are found in the pancreata of subjects with Type 2 diabetes and may contribute to β‐cell death. It is therefore necessary to study amylin secretion and kinetics to determine whether elevated levels of the peptide are due to elevated secretion, reduced clearance or both. The aim of this study was to measure amylin dynamics during an oral glucose tolerance test (OGTT). We also used a mathematical model of β‐cell activity to assess the secretion and kinetics of C‐peptide, insulin and amylin in humans during an OGTT. In particular, we were interested in characterizing the physiological meaning of one of the terms in the model, the amylin/C‐peptide co‐secretion factor (σ). The model has been used in several pathophysiological conditions and results indicate an elevated secretion and clearance of amylin in glucose‐intolerant states. Amylin clearance has been found to be similar to that of C‐peptide, and much slower than that of insulin. In this study, direct measurements of insulin and amylin secretion in five obese subjects yielded an estimate of the amylin/insulin co‐secretion factor of 0.004 with a standard deviation (SD) of 0.002. The point estimate of hepatic clearance was 80 ml min−1, which was much lower than that of insulin (507 ± 94 ml min−1). In addition, the estimated hepatic clearance was not significantly different from zero given its high SD of 213 ml min−1. The absence of hepatic extraction of amylin is therefore a plausible hypothesis, which is also supported by the similarity between amylin and C‐peptide clearances. This observation characterizes the physiological meaning of σ and suggests that this parameter is associated mainly with β‐cell secretion. © 1997 John Wiley & Sons, Ltd.

The presence of amyloid deposits in the pancreas was first described at the beginning of the 20th century. However, it was not until 1987 that the structure of the amylin molecule was identified. Amylin is a 37‐amino‐acid peptide hormone that is co‐secreted with insulin by the pancreatic β‐cells in response to a nutrient stimulus. It is deficient in patients with Type 1 diabetes and elevated in patients in the early stages of Type 2 diabetes, a condition which is characterized by hyperinsulinaemia. Elevation of plasma amylin levels has also been described in patients with impaired glucose tolerance, obese subjects and in pregnant women with both normal glucose tolerance and gestational diabetes mellitus. However, it appears that deficiencies of amylin secretion appear before those of insulin in patients in the later stages of Type 2 diabetes. Early experimental studies suggested that amylin inhibits basal insulin secretion, and induces insulin resistance in skeletal muscle, leading to the hypothesis that it has a role in the aetiology of Type 2 diabetes. However, a number of more recent experimental studies have indicated that amylin is a third active pancreatic islet hormone that works with insulin and glucagon to maintain glucose homeostasis. Amylin appears to regulate glucose inflow to the circulation by influencing the rate of gastric emptying, and thus the rate at which meal‐derived glucose enters the system, and also by inhibiting glucose release and hepatic glucose production in the postprandial period. © 1997 John Wiley & Sons, Ltd.

The minimum time control problem for achieving a steady state tracer concentration in a linear compartmental system is considered. The scalar input case is studied for the class of nonnegative and both upper bounded and unbounded inputs. A minimax strategy is applied to the resulting bang-bang and impulsive controls for increasing the robustness with respect to model parameter uncertainties. A case study on tracer glucose kinetics is presented. The performance of the proposed approach is compared to conventional minimax designs. The results show that the proposed input design reduces, in presence of large model parameter variations, the maximum time intervals necessary to achieve tracer concentrations close to the true steady state.

This paper describes a software for the automated generation of FORTRAN source code sub-routines for the numerical integration of non-linear differential equations describing dynamical systems. The use of directed graphs for representing the systems greatly simplifies the definition of models and allows an efficient use of symbolic differentiation rules for generating the source code for: i) the sensi-tivity equations for the state/output trajectories with respect to model parameters; ii) the differential equations for computing the adjoint variables of optimal control problems. Possible applications of this software include model building, sensitivity analysis, identification, optimal experiment design and numerical solution of optimal control problems.

Although it is generally accepted that islet amyloid polypeptide is cosecreted with insulin, relatively few data on its kinetics are available. We therefore studied the dynamics of islet amyloid polypeptide release following oral and frequently sampled intravenous glucose tolerance tests in comparison to insulin and C-peptide using mathematical model techniques in 14 control subjects, 10 obese and 11 hyper-tensive patients. The fractional clearance rate of islet amyloid polypeptide (0.034 ±0.004 min−1in control subjects, 0.058 ± 0.008 in the obese and 0.050 ± 0.008 in the hypertensive patients) was significantly different (p< 0.01) in each group compared with that of insulin (0.14 ± 0.03 min−1) and similar to that of C-peptide (0.061 ± 0.007 min−1), at least in the insulin-resistant subjects. Based on the insulin sensitivity index derived from the minimal model analysis of intravenous glucose tolerance test data, both the hypertensive (2.4 ±0.4 min−1/(μU/ml); p< 0.0005) and the obese (2.7 ±0.5; p< 0.001) patients demonstrated severe insulin resistance compared to control subjects (8.1 ± 1.3). Marked insulin hypersecretion was found in the hypertensive (57.6 ± 5.2 nmol · 1−1in 180 min; p< 0.001) and obese (60.8 ± 10.1; p< 0.003) patients in comparison with control subjects (32.4 ± 3.2). The release of islet amyloid polypeptide was significantly higher in the hypertensive (83.1 ± 16.6 pmol/1 in 180 min; p< 0.02) and obese (78.6 ± 13.1; p< 0.005) patients than in control subjects (40.5 ± 6.4). No correlation was found between islet amyloid polypeptide release and the insulin sensitivity index in any group. We conclude that, due to a significantly slower clearance of islet amyloid polypeptide in comparison to insulin, reliance on molar ratios between these two peptides might be misleading in the interpretation of islet amy-loid polypeptide secretion especially under non-steady-state conditions.

Plasma clearance of a tracer in peritoneal dialysis (PD) can be used to assess treatment adequacy without labour-intensive fluid collections. Accuracy and precision of plasma clearance estimates by the bolus injection technique depend on the estimation accuracy of the area under the concentration curve and the measurement precision of plasma concentrations. The first source of error is due to oversimplified, e.g. monoexponential, descriptions of plasma disappearance curves. The second source of error arises from the propagation of measurement errors to the parameter estimates.