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Background. The new General Medical Services (nGMS) contract was introduced in April 2004 to improve care of chronic diseases such as coronary heart disease (CHD) and reduce differences in treatment between patient subgroups. Objective. To determine whether the recording of CHD-related health indicators and prescribing of medicines have increased following the introduction of the nGMS contract and whether differences in the treatment of patients of differing age, gender and deprivation have been affected. Methods. A serial cross-sectional study carried out with 310 general practices in Scotland. The subjects were patients with CHD as identified by their GP. Main outcome measures were the recording of CHD-related health indicators and prescribing of medicines at pre- and post-contract time points (covariates: gender, age, co-morbidity, deprivation and practice size). Results. The recording of CHD-related quality indicators and prescribing increased dramatically (mean absolute increase of 17.1%) after the introduction of the nGMS contract. Post-contract, disparities between patient subgroups, continued for certain components of care. Women were less likely to be recorded than men in 9 of 11 components of care, with older patients (7 of 11 components of care) and the most deprived (4 of 11 components of care) also less likely to have a record than the youngest and least deprived, respectively. Conclusion. The introduction of the new contract was associated with a dramatic rise in the recording of CHD-related quality indicators. However, not all the population benefited equally for certain aspects of care. [ABSTRACT FROM AUTHOR]

Unlabelled: In modern medicine the diagnosis and prognosis of an abnormal metabolic condition is based on blood borne measurements involving one or more biomarker., Objective: This paper reports the development of a minimal negative feedback model for the description of longitudinal biomarkers concentrations for treatment of osteoporosis in postmenopausal women., Methods: Literature data were obtained from double-blind, placebo-controlled clinical trial over three years. There were four treatment groups: 1) Placebo, 2) Alendronate, 3) Conjugated Estrogen, and/or 4) Combination therapy. The negative feedback model consists of a biomarker and a companion controller. By considering the above basal biomarker values it is shown that the dynamics can be described by a second order differential equation without the involvement of biomarker production rate. The second order differential equation is also analogous to classical negative feedback servomechanism model with two parameters ω(n) and ξ. It was assumed that the rate constants defining the negative feedback model were equal which would set ξ to 0.707 with only ω(n) to be estimated., Results: ω(n) was estimated for both lumbar spine bone mineral density (BMD) and bone-specific alkaline phosphatase (BAP) in four treatments groups. The t(½) of BMD and BAP were estimated at 26.8 (0.30) and 9.4 (0.30) days respectively., Conclusions: The negative feedback model of BMD supports the mechanism whereby Conjugated Estrogen and Alendronate decrease the clearance rate constant of BMD analogous to increased apoptosis of osteoclasts. The linked negative feedback models facilitate a mechanism based prediction of BMD using the concentrations of the bone turnover marker BAP.

In this study we demonstrate the added value of mathematical model reduction for characterizing complex dynamic systems using bone remodeling as an example. We show that for the given parameter values, the mechanistic RANK-RANKL-OPG pathway model proposed by Lemaire et al. (J Theor Biol 229:293-309, 2004) can be reduced to a simpler model, which can describe the dynamics of the full Lemaire model to very good approximation. The response of both models to changes in the underlying physiology and therapeutic interventions was evaluated in four physiologically meaningful scenarios: (i) estrogen deficiency/estrogen replacement therapy, (ii) Vitamin D deficiency, (iii) ageing, and (iv) chronic glucocorticoid treatment and its cessation. It was found that on the time scale of disease progression and therapeutic intervention, the models showed negligible differences in their dynamic properties and were both suitable for characterizing the impact of estrogen deficiency and estrogen replacement therapy, Vitamin D deficiency, ageing, and chronic glucocorticoid treatment and its cessation on bone forming (osteoblasts) and bone resorbing (osteoclasts) cells. It was also demonstrated how the simpler model could help in elucidating qualitative properties of the observed dynamics, such as the absence of overshoot and rebound, and the different dynamics of onset and washout.

Aims: To determine whether the recording of diabetes-related health indicators has increased and differences diminished between age, gender and deprivation groups, following the introduction of the new General Medical Services contract (nGMS), an incentive- and target-based contract for UK family physicians., Methods: A serial cross-sectional study set in 310 primary care practices in Scotland serving a population of 1.5 million registered patients, focussing on diabetic patients. Data were taken immediately before the introduction of the nGMS and after it had been in place for 1 year., Results: One year after the introduction of the nGMS contract, there was a 54.2% relative increase in the number of patients electronically recorded as having diabetes. In addition, measurement of the quality indicators glycated haemoglobin (HbA(1c)), blood pressure, serum creatinine and cholesterol significantly increased (P < 0.05). Women were less likely than men to have HbA(1c)[odds ratio (OR) 0.85, 95% confidence intervals (CI) 0.80-0.91], serum creatinine (OR 0.90, 95% CI 0.84-0.96) and cholesterol recorded (OR 0.83, 95% CI 0.77-0.90) or achieve HbA(1c) (

The dyslipidemia and insulin resistance of type 2 diabetes can be improved by aerobic exercise. The effect of 6 months supervised exercise on very low-density lipoprotein (VLDL) apolipoprotein B metabolism was investigated in patients with type 2 diabetes. Moderately obese patients (n = 18) were randomized into supervised (n = 9) and unsupervised (n = 9) exercise groups. All patients were given a training session and a personal exercise program and asked to exercise four times per week at 70% maximal oxygen uptake for 6 months. Patients in the supervised group had a weekly session with an exercise trainer. VLDL apolipoprotein (apo)B metabolism was measured with an infusion of 1-(13)C leucine before and after 6 months of the exercise program. Supervised exercise for 6 months resulted in a significant within-group decrease in percent hemoglobin A1c (P < 0.001), body fat (P < 0.004), nonesterified fatty acid (P < 0.04), and triglycerides (P < 0.05) and an increase in insulin sensitivity (P < 0.01). There was a decrease in VLDL apoB pool size (160.8 +/- 42.6 to 84.9 +/- 23.2 mg, P < 0.01) and VLDL apoB secretion rate (11.3 +/- 2.6 to 5.5 +/- 2.0 mg/kg.d, P < 0.05) with no change in fractional catabolic rate. In a between-group comparison, the decrease in VLDL apoB secretion rate in the supervised group did not achieve significance. This study demonstrates that in type 2 diabetes, a supervised exercise program reduces VLDL apoB pool size, which may be due to a decrease in VLDL apoB secretion rate.

The aim of the GH-2000 project is to develop a method for detecting GH doping among athletes. Previous papers in the GH-2000 project have proposed that a forthcoming method to detect GH doping will need specific components from the GH/IGF-I axis and bone markers because these specific variables seem more sensitive to exogenous GH than to exercise. The present study examined the responses of the serum concentrations of these specific variables to a maximum exercise test in elite athletes from selected sports. A total of 117 elite athletes (84 males and 33 females; mean age, 25 yr; range, 18-53 yr) from Denmark, the United Kingdom, Italy, and Sweden participated in the study. The serum concentrations of total GH, GH22 kDa, IGF-I, IGF binding protein (IGFBP)-2, IGFBP-3, acid-labile subunit, procollagen type III (P-III-P), and the bone markers osteocalcin, carboxy-terminal cross-linked telopeptide of type I collagen (ICTP), and carboxy-terminal propeptide of type I procollagen were measured. The maximum exercise test showed, in both genders, a peak concentration of total GH (P < 0.001) and GH22 kDa (P < 0.001) by the time exercise ended compared with baseline, and a subsequent decrease to baseline levels within 30-60 min after exercise. The mean time to peak value for total GH and GH22 kDa was significantly shorter in males than females (P < 0.001). The components of the IGF-I axis showed a similar pattern, with a peak value after exercise compared with baseline for IGF-I (P < 0.001, males and females); IGFBP-3 (P < 0.001, males and females); acid-labile subunit [P < 0.001, males; not significant (NS), females], and IGFBP-2 (P < 0.05, females; NS, males). The serum concentrations of the bone markers ICTP (P < 0.001, males; P < 0.05, females) and P-III-P (P < 0.001, males and females) increased in both genders, with a peak value in the direct post-exercise phase and a subsequent decrease to baseline levels or below within 120 min. The osteocalcin and propeptide of type I procollagen values did not change during the exercise test. Specific reference ranges for each variable in the GH/IGF-I axis and bone markers at specific time points are presented. Most of the variables correlated negatively with age. In summary, the maximum exercise test showed a rather uniform pattern, with peak concentrations of the GH/IGF-I axis hormones and the bone markers ICTP and P-III-P immediately after exercise, followed by a subsequent decrease to baseline levels. The time to peak value for total GH and GH22 kDa was significantly shorter for females compared with males. This paper presents reference ranges for each marker in each gender at specific time points in connection to a maximum exercise test to be used in the development of a test for detection of GH abuse in sports.

Measurements of serum insulin-like growth factor I (IGF-I) and related markers are routinely used in the diagnosis and treatment of GH deficiency and excess. The validity of these markers for assessment of exogenous GH exposure in healthy adults is, however, unknown. We therefore conducted a double blind, placebo-controlled GH treatment trial in 99 healthy subjects [49 women and 50 men; mean +/- SE age, 25.6+/-0.6 (women)/25.7+/-0.6 yr (men)]. Blood was collected weekly during a 4-week treatment period (days 1-28), and the subjects were subsequently followed for additional 8 weeks (days 29-84). The treatment arms included: I) 0.1 IU/kg x day GH (n = 30; GH 0.1), II) 0.2 IU/kg x day GH (n = 29; GH 0.2), and III) placebo (n = 40). At baseline no gender-specific differences existed, except that the acid-labile subunit (ALS) levels were higher in females. Serum insulin-like growth factor I (IGF-I) levels in males receiving GH increased significantly through day 42 with no significant difference between the 2 doses. The absolute IGF-I response was significantly lower in females, and there was a clear dose-response relationship. ALS levels in males increased through day 30 (P < 0.001). In females ALS levels were only modestly increased on day 28 compared with those in the placebo group (P < 0.02). IGF-binding protein-3 (IGFBP-3) levels in males increased significantly in the GH 0.1 and the GH 0.2 groups on day 30 (P < 0.03), whereas no solid IGFBP-3 increase was detected in females. IGFBP-2 levels decreased insignificantly during GH exposure in both genders. A gender-specific upper normal range for each analyte was arbitrarily defined as 4 SD above the mean level at baseline. On the basis of IGF-I levels alone, GH exposure in the GH 0.2 group was detected in 86% of the males and in 50% of the females on day 21. On day 42 GH exposure was only weakly detectable in males and was not detectable in females. We conclude that 1) males are significantly more responsive than females to exogenous GH; 2) the increase in IGF-I is more robust compared with those in IGFBP-3 and ALS; 3) IGFBP-2 changes very little during GH treatment; and 4) among IGF-related substances, IGF-I is the most specific marker of supraphysiological GH exposure.

The effects of GH on bone remodeling in healthy adults have not been systematically investigated. An analysis of these effects might provide insights into GH physiology and might yield data useful for the detection of GH doping in sports. The aim of this study was to evaluate the effects of GH administration on biochemical markers of bone and collagen turnover in healthy volunteers. Ninety-nine healthy volunteers of both sexes were enrolled in a multicenter, randomized, double blind, placebo-controlled study and assigned to receive either placebo (40 subjects) or recombinant human GH (0.1 IU/kg day in 29 subjects and 0.2 IU/kg x day in 30 subjects). The treatment duration was 28 days, followed by a 56-day wash-out period. The biochemical markers evaluated were the bone formation markers osteocalcin and C-terminal propeptide of type I procollagen, the resorption marker type I collagen telopeptide, and the soft tissue marker procollagen type III. All variables increased on days 21 and 28 in the two active treatment groups vs. levels in both the baseline (P < 0.01) and placebo (P < 0.01) groups. The increment was more pronounced in the 0.2 IU/kg-day group and remained significant on day 84 for procollagen type III (from 0.53 +/- 0.13 to 0.61 +/- 0.14 kU/L; P < 0.02) and osteocalcin (from 12.2 + 2.9 to 14.6 +/- 3.6 UG/L; P < 0.02), whereas levels of C-terminal propeptide of type I procollagen and type I collagen telopeptide declined after day 42 and were no longer significantly above baseline on day 84 (from 3.9 +/- 1.2 to 5.1 +/-1.5 microg/L and from 174 +/- 60 to 173 +/- 53 microg/L, respectively). Gender-related differences were observed in the study; females were less responsive than males to GH administration with respect to procollagen type III and type I collagen telopeptide (P < 0.001). In conclusion, exogenous GH administration affects the biochemical parameters of bone and collagen turnover in a dose- and gender-dependent manner. As GH-induced modifications of most markers, in particular procollagen type III and osteocalcin, persist after GH withdrawal, they may be suitable markers for detecting GH abuse.

Patients with adult GH deficiency are often dyslipidemic and may have an increased risk of cardiovascular disease. The secretion and clearance of very low density lipoprotein apolipoprotein B 100 (VLDL apoB) are important determinants of plasma lipid concentrations. This study examined the effect of GH replacement therapy on VLDL apoB metabolism using a stable isotope turnover technique. VLDL apoB kinetics were determined in 14 adult patients with GH deficiency before and after 3 months GH or placebo treatment in a randomized double blind, placebo-controlled study using a primed constant [1-(13)C]leucine infusion. VLDL apoB enrichment was determined by gas chromatography-mass spectrometry. GH replacement therapy increased plasma insulin-like growth factor I concentrations 2.9 +/- 0.5-fold (P < 0.001), fasting insulin concentrations 1.8 +/- 0.6-fold (P < 0.04), and hemoglobin A1C from 5.0 +/- 0.2% to 5.3 +/- 0.2% (mean +/- SEM; P < 0.001). It decreased fat mass by 3.4 +/- 1.3 kg (P < 0.05) and increased lean body mass by 3.5 +/- 0.8 kg (P < 0.01). The total cholesterol concentration (P < 0.02), the low density lipoprotein cholesterol concentration (P < 0.02), and the VLDL cholesterol/VLDL apoB ratio (P < 0.005) decreased. GH therapy did not significantly change the VLDL apoB pool size, but increased the VLDL apoB secretion rate from 9.2 +/- 2.0 to 25.9 +/- 10.3 mg/kg x day (P < 0.01) and the MCR from 11.5 +/- 2.7 to 20.3 +/- 3.2 mL/min (P < 0.03). No significant changes were observed in the placebo group. This study suggests that GH replacement therapy improves lipid profile by increasing the removal of VLDL apoB. Although GH therapy stimulates VLDL apoB secretion, this is offset by the increase in the VLDL apoB clearance rate, which we postulate is due to its effects in up-regulating low density lipoprotein receptors and modifying VLDL composition.

Objectives: To investigate the effects of IGF-I and insulin at doses equipotent with respect to hypoglycaemic effect on IGF-I concentrations (free and bound), IGF binding proteins, catecholamines and potassium levels., Design: A glucose and amino acid clamp technique was used to investigate the effects of a 3 h intravenous infusion of either IGF-I 43.7 pmol/kg/min (20 micrograms/kg/h) or insulin 3.4 pmol/kg/min (0.5 mU/kg/min)., Measurements: Circulating levels of total IGF-I, free and bound IGF-I, Insulin, IGFBP-1, IGFBP-3, ALS, catecholamines and potassium were measured., Patients: 6 normal human volunteers aged 21-49., Results: During the IGF-I infusion, IGF-I levels increased (P < 0.01) (26.6 +/- 2.8-88.9 +/- 14.2 nmol/l) and insulin levels fell (P < 0.05) (16.7 +/- 2.9-7.2 +/- 1.6 mu/l). During the insulin infusion, insulin levels increased (P < 0.01) (11.7 +/- 1.6-56.7 +/- 16 mu/l) and there was no change in IGF-I. There was no significant change in IGFBP-3 or ALS during the IGF-I or insulin infusions. There was a significant (P < 0.05) fall in IGFBP-1 levels from 27.1 +/- 4.1-8.06 +/- 1.6 micrograms/l during the insulin infusion and a significant (P < 0.05) rise during the first 120 min of IGF-I infusion from 28.6 +/- 6.3-67.9 +/- 10.6 micrograms/l. There was a significant (P < 0.05) increase in free IGF-I and IGF-I bound to the 150 and 50 kD plasma fractions during the IGF-I infusion. At basal and the end of the IGF-I infusion adrenaline levels (pmol/l) were: 173 +/- 22 and 174 +/- 28; dopamine levels (pmol/l) were: 415 +/- 87 and 470 +/- 87; plasma potassium (mmol/l) was 4.2 +/- 0.06 and 3.56 +/- 0.13. At basal and the end of the insulin infusion adrenaline levels (pmol/l) were: 160 +/- 38 and 163 +/- 21; dopamine levels (pmol/l) were: 238 +/- 26 and 316 +/- 31; plasma potassium (mmol/l) was 4.2 +/- 0.07 and 3.92 +/- 0.17. There were no significant changes in plasma catecholamine concentrations with either infusion but potassium concentrations were significantly (P < 0.05) reduced during the IGF-I infusion., Conclusions: We conclude that an infusion of IGF-I resulted in increased levels of both free and bound IGF-I. IGF-I and insulin under conditions of adequate substrate supply have acute effects on IGFBP-1 and potassium physiology, but have little effect on IGFBP-3, ALS or catecholamines.

The pharmacokinetics of recombinant human insulin-like growth factor I (IGF-I) were studied in four healthy volunteers by a 3-h infusion at a rate of 20 micrograms.kg-1.h-1. A compartmental model was used to simulate the plasma "free" IGF-I and IGF-I associated with the 50- and 150-kDa plasma protein fractions. The model is based on the concept that free IGF-I and IGF binding proteins (IGFBPs) are the substrates for their own degradation and that they act as reservoirs for retention of IGF-I in the vascular compartment or inhibiting IGF-I action. The metabolic clearance rate (MCR) of free IGF-I is estimated as 2.62 +/- 0.94 ml.min-1.min-1 with a production rate of 4.75 +/- 1.74 mg/day (621.0 +/- 227.34 nmol/day). The simulation shows that higher concentrations of IGFBP-3 would increase the estimate of MCR for free IGF-I by reducing free IGF-I concentration. The model will be of value for simulation of dynamic profiles of free IGF-I and receptor-bound IGF-I in a variety of pathophysiological conditions.

Gestational diabetes affects 2-3% of pregnant women and is associated with foetal complications including macrosomia and an increased likelihood of developing diabetes in later life. We have therefore studied seven women with gestational diabetes and five control women both during the third trimester of pregnancy and again 2-3 months post-partum, using the minimal model analysis of the frequently sampled labelled ([6,6-2H2]-glucose) intravenous glucose tolerance test. Glucose tolerance (glucose Kd) was significantly reduced in the women with gestational diabetes compared with the normal pregnant women both in pregnancy (1.16 +/- 0.11 vs 1.78 +/- 0.23%/min; p < 0.05) and post-partum (1.47 +/- 0.22 vs 2.59 +/- 0.43%/min; p < 0.05) and increased significantly in the control women after delivery (p < 0.05). Glucose effectiveness was not significantly different between the women with gestational diabetes and the control group either during or after pregnancy. Insulin sensitivity was significantly lower during pregnancy than after delivery in the women with gestational diabetes (p < 0.05). There was no significant difference in basal insulin secretion in the two groups during pregnancy or post-partum. However, during pregnancy the control subjects significantly increased (p < 0.001) their insulin secretion over a period of 20 min in response to an intravenous glucose tolerance test (96.2 +/- 42.7 pmol/kg) compared with post-partum values (58.3 +/- 25.2 pmol/kg) while in the women with gestational diabetes insulin secretion was similar in pregnancy (65.5 +/- 9.3 pmol/kg) and after delivery (57.7 +/- 15.7 pmol/kg). These data suggest that the glucose intolerance in gestational diabetes compared to normal pregnancy is due to reduced insulin sensitivity and an impaired ability in gestational diabetes to increase insulin secretion in response to glucose.

The effect of infusions of recombinant insulin-like growth factor-I (IGF-I) (34, 103 or 688 pmol kg-1 min-1), insulin (3.4, 10.3 or 68.8 pmol kg-1 min-1) or combined infusions (34 pmol IGF-I + 3.4 pmol kg-1 min-1 insulin or 103 pmol IGF-I + 3.4 pmol kg-1 min-1 insulin) on glucose metabolism was investigated in dogs using a [3-3H]-glucose infusion and euglycaemic clamp. All insulin doses decreased glucose production rate (Ra) in a dose-dependent manner (P < 0.05). All IGF-I doses decreased glucose Ra (P < 0.05) but this decrease was not dose dependent. The decrease in glucose Ra with the combined infusion of 34 pmol kg-1 min-1 IGF-I + 3.4 pmol kg-1 min-1 insulin was greater than 34 pmol kg-1 min-1 IGF-I (P < 0.05) but not different from 3-4 pmol kg-1 min-1 insulin. All insulin and IGF-I doses increased glucose utilization rate (Rd) in a dose-dependent manner (P < 0.01). The increase in glucose utilization was greater following both combined infusions than with either component infused alone (P < 0.05). Although at the doses selected, insulin and IGF-I had similar effects on glucose utilization with additive effects when the two peptides were combined, IGF-I was less effective than insulin in suppressing glucose production.

The relationship between changes in ketone concentrations and leucine metabolism (seven obese subjects), glucose and alanine metabolism (seven obese subjects) was investigated using radioisotopic techniques after 12 h, 60 h and 2 weeks starvation. Leucine metabolism was also measured in five lean subjects after 12 h and 60 h starvation. In the obese subjects leucine concentration increased after 60 h starvation and leucine metabolic clearance rate, glucose and alanine concentration decreased (P < 0.05). Glucose and alanine production rate (Ra) decreased after 2 weeks (P < 0.05) but there was no change in leucine Ra after 60 h or 2 weeks. In the lean subjects leucine concentration, production rate and oxidation rate were increased after 60 h (P < 0.005, P < 0.05, P < 0.05). Ketone concentration was inversely related to alanine Ra (r = -0.51, P < 0.02) but was not related to measurements of protein metabolism in the obese subjects. This study demonstrates that the effect of short-term starvation on protein metabolism differs in lean and obese subjects. The decrease in glucose Ra during long-term starvation may be in part due to a decreased supply of alanine for gluconeogenesis.

A glucose kinetic model is described that contains insulin-independent and insulin-dependent pathways of glucose uptake and includes a saturating flux term for glucose transport into the cells by the glucose transporters. The rate of glucose utilization was estimated in control subjects and diabetic patients by use of a bolus of [3-3H]glucose. Diabetic patients were studied after three regimens of insulin therapy: 1) after 24 h of insulin withdrawal, 2) after conventional insulin therapy, and 3) after an overnight insulin infusion such that plasma glucose was maintained between 4 and 6 mmol/l. In addition, the model was used to simulate published results from glucose clamp experiments with a range of glycemic levels and insulin concentrations. Estimates of glucose utilization flux in diabetic patients and model simulation suggest that high plasma glucose concentrations in uncontrolled diabetic patients can be attributed to a high glucose production rate by the liver associated with a reduction in glucose metabolic clearance rate due to relative saturation of the available pool of glucose transporters.

A compartmental model for the simulation of in-vivo insulin-like growth factor one (IGF-I) kinetics and metabolism is presented. The model is based on the concept that IGF binding proteins (IGFBPs) act as a reservoir for IGF-I in plasma, thereby restricting its access to the extravascular space. The model is divided into two subsystems; a binding model for IGF-I and IGFBP, and an IGF-I clearance model, which includes the binding of IGF-I to IGF-I receptors. The non-linear differential equations describing the model are based on the law of mass action. Given the steady state condition, the linearized form of the model, describing tracer kinetics of IGF-I and IGFBPs is developed. It is demonstrated that using the available data, it is possible to assign values to the model parameters, thereby allowing simulation of the model to obtain information not accessible by direct observation.

The paper describes a software package for modelling and simulating compartmental systems based upon a generalisation of the equations of compartmental systems. The aim is a versatile package which can be used for rapid model development. Its use is first illustrated in a number of simple classical examples. The power of the software--and more generally the methodology--is demonstrated by showing its application in developing a model-based system for insulin planning for diabetic patients. The software has been written in Pascal and runs on IBM PC and compatible computers.

Glucose and leucine metabolism were investigated in 5 poorly controlled non-insulin-dependent diabetics (NIDDM) following an i.v. injection of 3-[3H]glucose and 1-[14C]leucine in the morning and evening. In the morning glucose concentration (11.2 +/- 0.8 mmol/l) (mean +/- SEM) and production rate (14.2 +/- 1.3 mumol/min/kg) were significantly greater (P less than 0.001, P less than 0.05) and glucose metabolic clearance rate (MCR) (1.3 +/- 0.2 ml/min/kg) significantly lower (P less than 0.05) than in a group of control subjects. Glucose concentration was lower in the evening (P less than 0.05) as a result of a decrease in glucose production rate (P less than 0.05). Leucine concentration and production rate were not significantly different from normal but leucine oxidation rate was increased (P less than 0.05). There was no diurnal variation in leucine metabolism. Since leucine production is a measure of protein breakdown, the higher morning glucose production rate was not due to an increased supply of gluconeogenic precursors from protein catabolism.

1. The effect of an infusion of sodium beta-hydroxybutyrate on leucine and alanine metabolism was investigated in dogs starved for 12 h. To determine whether the metabolic changes produced by this infusion were due to the resultant alkalaemia the effect of an equimolar infusion of sodium bicarbonate was also studied. 2. The sodium beta-hydroxybutyrate infusion reduced alanine concentration as a result of a decrease in alanine production rate and an increase in alanine metabolic clearance rate. The sodium bicarbonate infusion induced a small decrease in alanine concentration which was due to an increased metabolic clearance rate. Alanine production rate showed no change. This demonstrates that the fall in alanine concentration after a sodium beta-hydroxybutyrate infusion is due both to a ketone-specific inhibitory effect on alanine production rate and an increased metabolic clearance rate caused by the alkalaemia. 3. Leucine concentration was increased after the ketone infusion due to a small increase in production rate and there was a small increase in the rate of leucine incorporation into protein. Alkalaemia had no effect on leucine concentration or metabolism.

Leucine turnover was measured using [1-14C] L-leucine in three patients with classical maple syrup urine disease. There was measurable leucine oxidation although it was lower than in normal adults. Leucine production rate was greater than normal in all three patients with an increased rate of incorporation of leucine into protein and increased protein catabolism. These fluxes were both relatively insensitive to exogenous insulin.

Turnover rates of glucose, free fatty acids (FFA) and leucine have been measured in newly diagnosed, uncontrolled insulin-dependent diabetic (IDD) patients. The results have been compared with data collected from the same patients while on conventional insulin therapy as well as after overnight intravenous infusion of insulin with sustained normoglycaemia. The data have been analysed by compartmental and non-compartmental methods and the results have been compared with simultaneously collected data on respiratory exchange. Oxidation rates of 14C-labelled substrates have also been measured. Tracer studies were done on established diabetics after insulin withdrawal and subsequent intravenous infusion of insulin at different rates. The results confirm the in vivo importance of the glucose-fatty acid cycle, indicating that when glucose, FFA and ketone bodies are available in excess it is FFA and ketones that are metabolized in preference to glucose. The data emphasize the importance of increased production rates rather than decreased utilization rates in producing high concentrations of substrates in the plasma of insulin-deficient patients.

A simple model of the distribution and metabolism of insulin in vivo has been evaluated using data from insulin infusion into a group of normal subjects. The major rate-limiting step for access to degradation pathways is assumed to consist of binding of the ligand to a single population of insulin receptor sites, except that provision is made for the possibility of linear non-receptor-mediated degradation and for the phenomenon of negative cooperativity. The model has been shown to accommodate the non-linearity of insulin metabolism, allows, evaluation of receptor association and dissociation constants and provides for the first time an estimate of total accessible receptor number in the intact organism. For normal fasting man the model predicts 1.00 +/- 0.05 nmol accessible binding sites/kg (mean +/- SD).

Leucine production rate, metabolic clearance rate and oxidation rate were measured in 10 Type 1 (insulin-dependent) diabetic patients after 24 h insulin withdrawal, conventional insulin therapy and an overnight insulin infusion to maintain normoglycaemia, and in 10 control subjects. In the insulin-withdrawn patients, leucine concentration (259 +/- 17 mumol/l), production rate (2.65 +/- 0.29 mumol . min-1 . kg-1) and oxidation rate (0.69 +/- 0.10 mumol . min-1 . kg-1) were significantly greater (p less than 0.001; p less than 0.05; p less than 0.005 respectively) than corresponding values in control subjects (127 +/- 6; 1.81 +/- 0.12; 0.19 +/- 0.02). Following conventional insulin therapy, leucine concentration (162 +/- 12 mumol/l) and oxidation rate (0.43 +/- 0.05 mumol . min-1 . kg-1) were lower than after insulin withdrawal but were still significantly greater than in control subjects (p less than 0.05; p less than 0.005). Although leucine concentration, production rate and metabolic clearance rate were normal after an overnight insulin infusion, leucine oxidation rate was still greater than normal (0.34 +/- 0.06 mumol . min-1 . kg-1; p less than 0.05). These results suggest that increased leucine concentration in insulin deficiency is due to elevated leucine production rate caused by increased proteolysis, and that leucine concentration is restored to normal by insulin treatment.

This paper describes the principles and prototyping of a computer-based system being developed to assist in the management of diabetes mellitus. Unlike other approaches based upon mathematical modelling or the use of computer algorithms, this system adopts one derived from artificial intelligence, seeking to incorporate the dynamics of glucose and insulin in a manner which reflects their clinical importance. The resultant logical model (qualitative algebra) defines the relationships between changes in insulin dose and site and time of injection and glycaemic response. In this manner the computer-based system, implemented in Prolog, can be used to provide advice concerning insulin therapy by means of making qualitative predictions of patient outcome of blood glucose profile resulting from alternative insulin regimens.

To compare the metabolic characteristics and degradation of insulin tracers labeled unselectively, selectively at the A14 position (A14-monoiodoinsulin), and selectively at the B1 position (B1-monoiodoinsulin), we have followed the time course of disappearance of intact (immunoprecipitable [IP] and trichloroacetic acid [TCA] precipitable) iodoinsulin after bolus injection into greyhounds. We have used noncompartmental analysis to determine metabolic clearance rate (MCR) and apparent distribution space (DS). We have also measured the appearance of non-IP- and non-TCA-precipitable fragments, and have developed a mathematical model using compartmental analysis to explain the observed differences. B1-Monoiodoinsulin has a significantly higher MCR (16.3 ml/min/kg) than both A14-monoiodoinsulin (10.6 ml/min/kg) and unfractionated tracers (7.6 ml/min/kg) as determined by immunoprecipitation, and reaches the values observed for native insulin in greyhounds. MCR values obtained by TCA precipitation are approximately one-half of those obtained by IP for all 3 tracers. The concentration of non-IP fragments is significantly lower with B1-monoiodoinsulin than with the other tracers. Compartmental analysis suggests this to be due to greater intracellular retention of the B1 moiety during the experimental period. We conclude that: (1) by the criterion of MCR, B1-monoiodoinsulin seems to behave more like native insulin than other preparations tested; (2) the reduced MCR of A14-monoiodoinsulin raises doubts about its validity as a tracer for insulin; (3) a high-molecular-weight product of insulin degradation, which includes both the B1 and the A14-A19 regions of the molecule, is released into the circulation; and (4) smaller fragments containing A14-A19 reappear in the circulation more rapidly than fragments containing B1.(ABSTRACT TRUNCATED AT 250 WORDS)