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Assessment of Insulin Sensitivity from Steady-State and Dynamic Tests Berson & Yalow (1970) defined insulin resistance as 'a state in which greater-than-normal amounts of insulin are required to elicit a quantitatively normal response'. Several books cover all the biological, physiological and pathological aspects of impaired insulin action (e.g. Moller 1993, Reaven & Laws 1999, Krentz 2002, Porte et al. 2003, DeFronzo et al. 2004) and stress its possible role in the development of...

Metabolic fluxes in healthy liver

Hepatic glucose fluxes play a pivotal role in maintaining normal glucose homeostasis in the liver. Hepatocytes can store large amounts of glucose in the form of glycogen, and rapidly release this glucose from its glycogen stores into the circulation by glycogenolysis. In addition, the liver and, to a minor extent, the kidney take up lactate, glycerol and amino acids and convert these substrates to glucose by gluconeogenesis, which also contributes to glucose production. The simultaneous nature...

References

Abe, T, Kawakami, Y, Sugita, M, Yoshikawa, K, Fukunaga, T (1995) Use of B-mode ultrasound for visceral fat mass evaluation comparisons with magnetic resonance imaging, Appl Human Sci, 14, 3, 133-139 Aldefeld, B, Bornert, P, Keupp, J (2006) Continuously moving table 3D MRI with lateral frequency- encoding direction, Magn Reson Med, 55, 5, 1210-1216 Anderson, P J, Chan, J C, Chan, Y L, Tomlinson, B, Young, R P, Lee, Z S, Lee, K K, Metreweli, C, Cockram, C S, Critchley, J A (1997) Visceral fat and...

Genetic risk

The relative genetic risk ( R) of an inherited disease is defined as the recurrence risk for a relative of an affected person divided by the risk for the general population it can either be risk to a sibling ( S) or to an offspring ( O). The higher the s the easier is it to find (map) the genetic cause of the disease. The s value for cystic fibrosis is approximately 500, for type 1 diabetes, 15 and for type 2 diabetes, 3. It is therefore not surprising that cystic fibrosis was the first disease...

Measurement of symptoms

Symptoms of hypoglycaemia were first reported in relation to tumours of the pancreas (Wilder 1927). As early as 1927, the symptoms of hypoglycaemia were recognised as forming two groups the first occurring during mild reactions comprising anxiety, weakness, sweating, hunger, tremor and palpitations and the second more severe group including mood changes, speech and visual disturbances, drowsiness, convulsions and coma (Harrop 1927). It was also noted that some patients did not experience the...

Calculating glucose thresholds for hormone release

Glucose thresholds for release of counterregulatory hormones or onset of other responses to hypoglycaemia are defined as the plasma glucose concentration at which the response is fisrt significant. They can thus only be reliably identified in slow reductions in plasma glucose, preferably stepped, as described above. The critical issue is to decide before starting what determines a significant change. This can either be to a specific value or by a predefined degree of increase. The gold standard...

Investigating the pathogenesis of problematic hypoglycaemia

In order to investigate counterregulatory mechanisms, it is important to produce hypogly-caemia in a controlled laboratory setting where physiological and cognitive responses can be measured accurately and reproducibly. Two variables can be measured the ability to counterregulate, in which the subject's ability to arrest a falling glucose is determined and the elements of the counterregulatory responses themselves, in which the hypoglycaemic challenge is strictly controlled by the investigator,...

Other sources of bias and error

Many patients with diabetes have complications leading to reduced visual acuity, and this requires that the print size of self-administered questionnaires is larger than that used in other populations, to ensure that misreading biases are not introduced. Likewise, other sources of bias should be considered and eliminated, such as with tools designed to assess quality of life, where a relative or friend of the patient may fill in the form for them. The prevalence of some forms of diabetes is...

Whole body fat distribution subcutaneous and visceral fat

Along with the fat ingestion in the postprandial state, the lipolysis from different adipose tissues within the human body is the main source of circulating FFA in fasting conditions. Even though the total fat mass determines the plasma pool of FFA and thereby the FFA flux from adipose to non-adipose tissue (Lewis et al. 2002), there are differences in the relationship of subcutaneous and visceral fat depots to features of peripheral and hepatic insulin sensitivity (Misra et al. 1997). Visceral...

Quantitative sensory testing

QST consists of procedures requiring a power source, where the intensity and characteristics of the stimuli are well controlled and where the detection threshold is determined in parametric units that can be compared with established 'normal' values (Arezzo 2003). QST measures can be used to identify the sensory modalities affected and to estimate the magnitude of the deficit. QST measures of vibration, thermal and pain thresholds have proven valuable in identifying diabetic patients with...

Practical description

Normally mercury-filled silatic strain gauges are used, connected to a plethysmograph. The strain gauge is attached to the upper part of the forearm and inflatable cuffs are placed on the upper arm and the wrist. The distance of the strain gauge from the elbow should be recorded if measurements are repeated at different time points. The forearm should be placed above the right atrium to allow venous emptying between measurement cycles. With the forearm placed above the level of the right...

Body fat distribution and insulin resistance Skeletal muscle intramyocellular lipids

Overabundance of plasma triglycerides and free fatty acids entering the circulation by lipol-ysis from adipose tissue or by ingestion from food is frequently associated with pathophys-iology of insulin resistance and diabetes mellitus (Defronzo 2004). Results of radioactive tracer and stable isotope dilution studies have suggested that both hepatic and peripheral muscle tissues are involved in the development of insulin resistance (Defronzo 1988). Focusing on glucose uptake in skeletal muscle,...

Tracers for the study of adipose tissue lipolysis Free fatty acids

Free fatty acids (FFAs) are the major lipid fuel in the circulation, with a relatively high flux rate that can be estimated at approximately 100g day in healthy adults (Miles et al. 2004). The use of tracers for the study of FFA kinetics is nearly 50 years old (Frederickson & Gordon 1958), but there has been a renewed interest in FFA metabolism in recent years because of evidence that elevated FFA levels are likely mediators of insulin resistance (Boden et al. 1991), endothelial dysfunction...

Pathophysiology

In health, the human body protects itself from clinically important hypoglycaemia very efficiently through a series of physiological and neuroendocrine responses, collectively described as 'counterregulation' (Amiel & Gale 1993). The major components of the counterregulatory hormone responses are shown in Figure 5.1. Blood glucose concentrations are normally very strictly regulated at 3.5-7 mmol l despite massive fluctuations in the rates at which tissues utilise glucose (rest vs exercise)...

Continuous glucose monitoring CGMS

Even with the most intense capillary glucose monitoring, there are vast periods of time when patients are unaware of their glucose values. The emergence of continuous glucose monitoring technologies has introduced new possibilities for measuring exposure to hypo-glycaemia in terms of duration and severity. Continuous glucose monitors use a variety of techniques to measure interstitial glucose. The most commonly used method uses a subcutaneous sensor coated with glucose oxidase, which reacts...

Perturbation of metabolic flux control the role of substrate overabundance

It is well known that increased circulating triglycerides and FFA are frequently associated with pathophysiology of insulin resistance and diabetes mellitus. Searching for the mechanism of their action on glucose metabolism, Sir Randle et al. 1963 observed that elevated circulating free fatty acids FFA impair skeletal muscle glucose uptake. The results of his studies allowed him to postulate the hypothesis that substrate competition for mitochondrial oxidation is the major mechanism involved in...

Radioactive vs stable isotopes

The study of amino acid kinetics is typically concerned with measuring the flow of carbon and or nitrogen. The choice of whether to use radioactive or stable isotopes typically depends on an investigator's experience, the research question s being asked and the facilities that are available. We consider here three factors that have likely contributed to the increased use of stable isotopes over radioactive isotopes. First, concerns for safety and improvements in nuclear magnetic resonance...

Exercise intolerance

In diabetic patients without evidence of heart disease, but with asymptomatic vagal CAN, exercise capacity greatest tolerable workload and maximal oxygen uptake , heart rate, blood pressure, cardiac stroke volume and hepatosplanchnic vascular resistance are diminished. Figure 16.1 Test battery for the detection and characterisation of cardiovascular autonomic neuropathy CAN . Figure 16.1 Test battery for the detection and characterisation of cardiovascular autonomic neuropathy CAN . A further...

Homa B Formulation

As with the HOMA method for insulin resistance see Chapter 3 , the calculation of the HOMA -cell function index HOMA-B requires only fasting glucose and insulin measurements. A model-based version of the method HOMA2, http www.dtu.ox.ac.uk homa web search keywords homa calculator,site dtu.ox.ac.uk is recommended, although a formula is also available HOMA-B constant X fasting insulin fasting glucose - 3.5 Matthews et al. 1985 . The advantages of the HOMA2 computer index have not been...

Liver intrahepatic lipids

As with skeletal muscle, elevated circulating free fatty acids FFA are associated with hepatic features of insulin resistance increased fasting endogenous glucose production EGP Hundal et al. 2000 , insufficient suppression of EGP in the postprandial state Singhal et al. 2002 Krssak et al. 2004 and defects in hepatic glycogen synthesis Krssak et al. 2004 in type 2 diabetes. Studies in young healthy volunteers have shown that experimentally elevated FFA concentration increased gluconeogenesis...

Thermal thresholds

Although most mechanoreceptors and free nerve endings can be stimulated by thermal energy, true cutaneous thermoreceptors are orders of magnitude more sensitive to shifts in temperature. The sensation of pain can be driven by high-intensity stimulation of thermore-ceptors, especially those sensitive to warming this activation can be assessed by measuring heat-pain thresholds Yaritsky et al. 1995 . As is the case with vibration, altered thermal thresholds have been well documented in patients...

Introduction

Diabetic autonomic neuropathy DAN may affect any organ innervated by the autonomic nervous system. Although DAN has been appreciated as a clinical entity since the classic report by Rundles 1945 , in the past it has received less attention than peripheral sensorimotor neuropathy. This is due on one hand to the fact that the onset of clinical features is insidious and severe clinical symptoms usually occur relatively late in the course of diabetes, and on the other hand, because non-invasive,...

Hovorka R. Isec Calculating Insulin Secretion Program Http Www.soi.city.ac.uk Sg331.

Potassium Glucose Transporter

Methods for the Assessment of p-Cell Function In Vivo The P cell plays a key role in the maintenance of glucose homeostasis and P-cell dysfunction is a characteristic feature of many states of glucose intolerance. Thus, the assessment of P-cell function is of fundamental importance in the study of metabolic disorders, particularly type 2 diabetes, and in the evaluation of drugs to treat P-cell dysfunction. At the present time, P-cell function continues to be very actively studied, as strategies...

Applications of PET for the assessment of skeletal muscle metabolism

By combining PET and the glucose-insulin clamp technique, insulin resistance for glucose was shown to localise in skeletal muscle in type 1 and type 2 diabetes Nuutila et al. 1993 Utriainen et al. 1998 . Using compartmental modeling, insulin is shown to affect transport and phosphorylation but not extracellular kinetics, with the transport step becoming the main site of control Kelley et al. 1999 Bertoldo et al. 2001 . Skeletal muscle free fatty acid uptake measured using 18-F-FTHA under...

Serious adverse event reporting

The purpose of documenting adverse events AEs serious adverse events SAEs is to acquaint pharmacovigilant departments of pharmaceutical companies and regulatory authorities with data helping to identify, document and report on the safety and tolerability of pharmaceutical agents being tested in clinical studies. For that reason, the terms 'AE' and in particular 'SAE' have to be used in a very strict sense only. By definition, AEs are untoward clinical events experienced by a study participant...

Fluorescein angiography of the fundus

Fundus Angiography Diabetic Retinopathy

No other single technique has had more impact on retinal investigation than fundus photography with the dye fluorescein. It has contributed to the diagnosis and treatment of chorioretinal diseases, elucidated poorly understood retinal diseases and served as an indispensable research modality. Sodium fluorescein is a yellow-red dye with a molecular weight of 376.67. It is used in 10 or 25 sterile aqueous solution. When injected, usually into the antecubital vein, 80 of it is bound to plasma...

Tdm

Bad control short term long amp short term good control good control Figure 11.12 Hepatic Glycogen Accumulation in Healthy and Diabetic Patients Rates of postprandial hepatic glycogen accumulation as measured in healthy men CON Krssak et al. 2004 and patients with type 2- and type 1 diabetes mellitus T2DM Krs's'a'k et al. 2004 T1DM Bischof et al. 2001, 2002 . A 50-60 decrease in this measure was observed by natural abundance 13C MR spectroscopy in both pathologies. Partial improvement was...

Standardised indices of insulin sensitivity derived from the M value

For purposes of comparison, M values should be standardised Ferrannini amp Mari 1998 . The steady state rate of whole body glucose metabolism is frequently normalised for bodyweight Mbw , fat free mass Mffm , rate of resting energy expenditure Mree and steady state plasma insulin concentration during the clamp M I Bergman etal. 1985 Ferrannini amp Mari 1998 . Normalisation of the M value for the mean steady state concentration of plasma glucose yields the metabolic clearance rate of glucose MCR...

Application of muscle morphology in type diabetes

Imcl Diabetes

Insulin resistance and type 2 diabetes are associated with a number of morphological characteristics in skeletal muscle. In humans, muscle fibre composition is more mixed than in rodents Johnson et al. 1973 . This has implications for many biochemical and metabolic abnormalities observed in studies of crude muscle extracts, as the functional and metabolic properties of muscle are to a large extent determined by its fibre type composition. Using the myofibrillar ATPase histochemical staining...

Albumin excretion

The hallmark of diabetic nephropathy is the progressive rise in urinary protein excretion, which is primarily of glomerular origin. Our understanding of the natural history of diabetic nephropathy was revolutionised by the development of immunoassays specific for albumin and capable of detecting small mg l amounts, so-called microalbuminuria Keen amp Chlou-verakis 1963 . In clinical practice, urine albumin and creatinine are measured in a non-timed preferably early morning urine sample, and the...

Electrophysiology

Whole nerve electrophysiological procedures e.g. NCV, F-waves, sensory and or motor amplitudes have emerged as important methods for tracing the onset and progression of diabetic neuropathy Bril 2003 . Typically, neurophysiological studies show a reduction in the amplitude of sensory action potentials, which is most extreme in the lower limbs. Multiple consensus panels have recommended the inclusion of electrophysiology in the evaluation of DPN, as well as the use of these procedures as...

Dalla V.m. Masiero A. Roiter A.m. Et Al Is Podocyte Injury Relevant In Diabetic Nephropathy Studies In Patients With

Anderson S, Blouch K, Bialek J, Deckert M, Parving HH, Myers BD 2000 Glomerular permselectivity in early stages of overt diabetic nephropathy Kidney Int 58, 2129-2137 Annet L, Hermoye L, Peeters F, Jamar F, Dehoux JP, Van beers BE 2004 Glomerular filtration rate, an assessment with dynamic contrast-enhanced MRI and a cortical-compartment model in the rabbit kidney J Magn Reson Imaging 20, 843-849 Arun CS, Stoddart J, Mackin P, MacLeod JM, New JP, Marshall SM 2003 Significance of...

Coupling nitrogen balance and isotope tracers

Measurements of total nitrogen intake and output can be used to calculate protein nutritional status Leverton amp Gram 1949 Hegsted 1978 . This approach is based on principles of chemical mass-balance, and although practical matters concerning collecting total nitrogen waste make this method difficult to implement, measurements of nitrogen balance generally permit a reliable determination of protein homeostasis. Use of the method requires special consideration since urinary nitrogen may occur...

Pancreatic clamp tests

In order to achieve a maximal possible suppression of endogenous insulin, glucagon and growth hormone release during hyperinsulinaemic clamp tests, a concomitant infusion of somatostatin can be applied Gottesman etal. 1982 Best etal. 1983 Basu etal. 2000 . Glucose clamp tests applying an infusion of somatostatin are commonly referred to as pancreatic clamp tests. Most investigators start the somatostatin infusion a few minutes before or simultaneously with the start of the insulin infusion. The...

Using rates of amino acid flux to determine wholebody protein turnover

Incorporation 13c Leucine

As noted earlier in this section, investigators are faced with several choices regarding measurements of amino acid flux and protein turnover. One of the more widely applied methods for quantifying amino acid and protein turnover centres on the use of a primed-infusion of 1-13C leucine Figure 10.2 . The flux of an amino acid e.g. leucine is described using the equation where Q is the rate of amino acid turnover in plasma or the flux , S is the rate of incorporation of the amino acid into...

Computed Tomography CT

Total Body Fat

Signal intensity in the CT images corresponds to the linear attenuation coefficient, which depends on physical properties including density of tissue within the volume of interest. Signal intensity is expressed in so-called computed tomography numbers or Hounsfield units HU , which range from -1,000 to 3,095 4,096 values . Based on their density and the resulting differences in X-ray attenuation, muscle and fat tissue display different ranges of intensity -190 to -30 HU for fat and 0 to 100 HU...

Optical coherence tomography OCT

This new technique for high-resolution cross-sectional imaging of various ocular structures was introduced in 1991. With an axial resolution of 10 mu, it provides the best resolution of retinal architecture of any imaging technique currently available. Information may be stored on computer disks and easily accessed in the future. This feature makes OCT particularly useful in the assessment, diagnosis and treatment of macular disease. The limitations of OCT include the inability to obtain...

Dhap

Glucose Enrichment

Figure 8.2 Metabolic model showing the principal exchange reactions that result in enrichment of glucose-6-phosphate and gluconeogenic precursors from 2H2O. 1 glucose-6-phosphate isomerase 2 phosphoglucomutase 3 transaldolase 4 triose phosphate isomerase. glucose, glycogen or gluconeogenesis . Under fasting conditions, when the liver is a net exporter of glucose, enrichment of plasma glucose position 2 represents all glucose derived from G6P. Under isotopic steady state conditions, enrichment...

Bernard Landau Md

Amiel BSc, MD, FRCP, RD Lawrence Professor of Diabetic Medicine, Gene and Cell Based Therapy, Diabetes Research Group, Diabetes, Endocrinology and Metabolism, King's College London School of Medicine, London, UK Henning Beck-Nielsen MD, DMSc, Head of the Department of Endocrinology, Odense University Hospital, Professor of Endocrinology, University of Southern Denmark, and Head of the Danish PhD School of Molecular Metabolism, Odense, Denmark Ayad Al-Bermani MD, Specialist...

Fasted state net glucose synthesis from hepatic GP

Nmr Spectra Paracetamol

Under these conditions, hepatic G6P is assumed to be entirely derived from gluconeogenesis and glycogenolysis activities and to be the sole source of plasma glucose synthesis, as shown in Figure 8.3. Because of extensive G6P-F6P exchange, position 2 is assumed to be enriched to the same level as body water and therefore it represents all G6P sources. Meanwhile, position 5 enrichment reflects the total gluconeogenic contribution. On this basis, the ratio of position 5 to position 2 enrichment H5...

Tracers for the study of triglyceriderich lipoprotein kinetics Chylomicrons

Chylomicrons are large lipoprotein particles that are formed by the small intestine during fat absorption. The amount of lipid fuel that traverses the circulation in the form of chylomicrons obviously varies with dietary fat consumption. In individuals on high-fat diets, however, it can equal or exceed FFA flux Miles et al. 2004 . The triglyceride transported in chylomicrons is metabolised by LPL, which is widely distributed in tissues but is most abundant in adipose tissue and skeletal muscle...

Blood sampling site arterial venous or arterialised venous blood sampling

Matched hyperinsulinaemia rates of whole body glucose metabolism can only be directly compared among individuals if the concentration of glucose perfusing their glucose utilising tissues is the same Bergman etal. 1985 . The concentration of plasma glucose physiologically declines during the perfusion of glucose utilising tissues. In addition, pancreatic insulin secretion is regulated by the arterial blood glucose concentration. Early studies applying the glucose clamp technique measured the...

Ncv

NCV is only gradually diminished by DPN, with estimates of a loss of 0.5m s-1 year-1 Arezzo 1997 . In a 10-year natural history study of 133 patients with newly diagnosed type 2 diabetes, NCV deteriorated in all six nerve segments evaluated, but the largest deficit was 3.9 m s for the sural nerve peroneal motor NCV was decreased by 3.0 m s over the same period Partanen 1995 . A similar slow progression of change in NCV was detected in the diabetes control and complications trial DCCT DCCT...

Limitations of human myotubes

Primary Cell Culture Satellite Cell

Cell culture techniques are dependent on aseptic conditions. The laboratory has to be equipped with the necessary cell culturing facilities and has to have good laboratory practice GLP . Although the technique seems simple, success with cultures of human myotubes depends on technicians with appropriate aseptic skills and the ability to diagnose problems as they arise. It is important to realise that we are dealing with a primary culture system, with restrictions such as limited lifespan of...

Principles of modeling PET tracer kinetics and modeling

Analysis of the radiation emitted by an organ allows us to estimate its functional parameters. PET is currently the only technique that permits noninvasive quantification of regional tissue perfusion, glucose and fatty acid metabolism, protein synthesis and oxygen consumption. Sequential images are acquired after tracer injection, monitoring the distribution of the tracer in the system of interest. Regions are drawn over the organ under study to obtain tissue-specific time-activity curves....

The Snellen chart

Snellen Chart Hcvd

This chart is named after a Dutch ophthalmologist 1834-1908 . It consists of a series of letters of diminishing size as in Figure 19.1a. Each letter has an overall size five times the thickness of the lines composing the letter. The results of the test are expressed as a fraction, in which the numerator is the testing distance 6 m and the denominator is the distance at which a normal observer would be able to read the letter. Other test types, which are designed to be applicable to any...

Magnetic Resonance Imaging MRI and spectroscopy

Mri Spectroscopy Show Muscle

Positioning of measured samples in strong homogeneous magnetic fields forces protons within the sample to align according to the direction of the magnetic field and thus create a macroscopic magnetisation of the sample. Interaction of spins with externally applied radiofrequency RF waves at the resonant frequency changes the magnitude and direction Figure 13.3 Assessment of Abdominal Fat Storage by Computed Tomography CT Representative cross-sectional abdominal CT scans of a lean A and an obese...

Percutaneous needle biopsy of skeletal muscle

Needle Muscle Biopsy

Extensive investigation of the metabolism of normal and abnormal tissue requires a simple method for tissue sampling. The percutaneous muscle biopsy technique developed and introduced by Bergstrom in the 1960s provides a simple and repeatable sampling method Bergstrom 1962, 1975 , which has made skeletal muscle one of the few tissues suitable for direct studies of structure and metabolic functions in human subjects. The percutaneous muscle biopsy procedure has been used widely to study many...

Silent myocardial infarction and ischaemia

In view of the increased prevalence of coronary artery disease CAD in diabetic patients, it is difficult to differentiate between the impact of coronary ischemia and CAN on cardiac autonomic function. In other words, silent ischemia in diabetic patients may either result from CAN or from autonomic dysfunction due to CAD itself, or both. In the Framingham study, the rates of unrecognised myocardial infarctions were 39 in diabetic subjects and 22 in non-diabetic subjects, but the difference was...

Vldl

Tracer Techniques Biology

Very low density lipoproteins VLDL are of interest for two reasons. First, they are the obligate precursor of low density lipoproteins LDL Dietschy et al. 1993 . Second, together with chylomicrons, VLDLs represent the major vehicle for transport of triglycerides in the circulation. VLDL triglyceride secretion by the liver is controlled to some extent by the supply of FFA to that tissue Lewis et al. 1995 , with additional acute regulation by insulin Sparks amp Sparks 1994 . Hepatic VLDL...

Clinical Assessment Symptoms

Many patients have difficulty in describing the symptoms of neuropathy. Pain and paresthe-siae are personal experiences, but there is marked variation in the description of symptoms between individuals with similar pathological lesions. This has important implications for the assessment of symptoms Huskisson 1976 clearly stated that 'pain is apersonal psychological experience and an external observer can play no part in its direct measurement.' When recording symptoms in clinical practice,...

Bicentennial

Copyright 2007 John Wiley amp Sons Ltd, The Atrium, Southern Gate, Chichester, Email for orders and customer service enquiries cs-books wiley.co.uk Visit our Home Page on www.wiley.com All Rights Reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning or otherwise, except under the terms of the Copyright, Designs and Patents Act 1988 or under the terms of a licence...