Chapter 11 - Insulin Modelling Toffolo, Gianna Maria; Cobelli, Claudio
Modelling Methodology for Physiology and Medicine,
2001
Book Chapter
Insulin is the primary regulator of glucose homeostasis. It is secreted by pancreatic β-cells into the portal vein in response to a rise in glucose concentration. Before reaching the systemic ...circulation, it passes through the liver, where a consistent fraction, approximately 50%, is degraded. The residual insulin reaches the target organ or tissues, such as liver, muscle, and adipose tissue, where it exerts its hypoglycaemic action to promote glucose uptake and inhibits hepatic glucose production before being eliminated by the liver and by other organs, such as the kidney. Insulin action depends on insulin concentration in proximity of the insulin-sensitive cells. This is the result of three processes: pancreatic secretion, hepatic extraction, and insulin kinetics. In this chapter, a number of models are reviewed among the various types proposed in the literature to describe the insulin system at different levels (single cell, population of cells, single organ or tissue, whole body) with different purposes, such as qualitative and quantitative description, understanding, simulation, and estimation of relevant fluxes or parameters.
Aims/hypothesis
Diabetic nephropathy is a major diabetic complication, and diabetes is the leading cause of end-stage renal disease (ESRD). Family studies suggest a hereditary component for diabetic ...nephropathy. However, only a few genes have been associated with diabetic nephropathy or ESRD in diabetic patients. Our aim was to detect novel genetic variants associated with diabetic nephropathy and ESRD.
Methods
We exploited a novel algorithm, ‘Bag of Naive Bayes’, whose marker selection strategy is complementary to that of conventional genome-wide association models based on univariate association tests. The analysis was performed on a genome-wide association study of 3,464 patients with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study and subsequently replicated with 4,263 type 1 diabetes patients from the Steno Diabetes Centre, the All Ireland-Warren 3-Genetics of Kidneys in Diabetes UK collection (UK–Republic of Ireland) and the Genetics of Kidneys in Diabetes US Study (GoKinD US).
Results
Five genetic loci (
WNT4/ZBTB40-
rs12137135,
RGMA/MCTP2-
rs17709344,
MAPRE1P2-
rs1670754,
SEMA6D/SLC24A5-
rs12917114 and
SIK1-
rs2838302) were associated with ESRD in the FinnDiane study. An association between ESRD and rs17709344, tagging the previously identified rs12437854 and located between the
RGMA
and
MCTP2
genes, was replicated in independent case–control cohorts. rs12917114 near
SEMA6D
was associated with ESRD in the replication cohorts under the genotypic model (
p
< 0.05), and rs12137135 upstream of
WNT4
was associated with ESRD in Steno.
Conclusions/interpretation
This study supports the previously identified findings on the
RGMA
/
MCTP2
region and suggests novel susceptibility loci for ESRD. This highlights the importance of applying complementary statistical methods to detect novel genetic variants in diabetic nephropathy and, in general, in complex diseases.
A mathematical model of zinc metabolism in six healthy women (average age: 30 +/- 11 y) was developed by using stable isotopes of zinc. After equilibration on a constant diet containing 7.0 mg Zn/d, ...an oral tracer highly enriched in 67Zn and an intravenous tracer highly enriched in 70Zn were administered simultaneously. Multiple plasma and 24-h urine samples were collected for the next 7 d with complete fecal collections for 11 d. Tracer-trace ratios in plasma, urine, and feces were calculated from isotope ratios of 67Zn to 66Zn and 70Zn to 66Zn measured by using inductively coupled plasma-mass spectrometry. An a priori identifiable model composed of seven compartments was developed to describe the kinetics of both tracers as well as that of naturally occurring zinc. The parameters of the model were fitted to the data by using the SAAM-CONSAM modeling software and were estimated with good precision. Several important, not directly measurable zinc variables were estimated (mean +/- SEM) from the model including the fractional absorption from the gastrointestinal tract (0.279 +/- 0.043), the rates of endogenous secretion (2.79 +/- 0.49 mg/d) and excretion (2.01 +/- 0.35 mg/d), the fractional turnover rate of the plasma pool (131 +/- 20/d), and the sizes (7.2 +/- 1.2 and 77.1 +/- 6.4 mg) and fractional turnover rates (22.3 +/- 7.1 and 1.49 +/- 0.18/d) of the fast and slow tissue pools equilibrating with the plasma, respectively.
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