Conditions associated with insulin resistance Atherosclerosis Central obesity PCOS Hypertension Type 2 diabetes Hypercoagulation/ impaired fibrinolysis Hyperinsulinaemia Microalbuminuria Endothelial dysfunction Low grade chronic systemic inflammation PCOS - Polycystic Ovarian Syndrome Dyslipidaemia INSULIN RESISTANCE NOTE: This slide contains animation – activated via one mouse-click. Insulin resistance is associated with the development of a clustering of metabolic disorders, including type 2 diabetes, obesity, hypertension, dyslipidaemia, and atherosclerosis, known as the insulin resistance syndrome (also known as the metabolic syndrome or syndrome X). Adapted from DeFronzo. Diabetes Care 1991; 14: 173-194

Progressive decline of HOMA beta-cell function over time 100 Start of treatment 80 60 HOMA beta-cell function (%) p<0.0001 40 20 The United Kingdom Prospective Diabetes Study (UKPDS) compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment with diet on the risk of microvascular or macrovascular complications in patients with type 2 diabetes in a randomised controlled trial. The study showed that beta-cell function deteriorated over six years in the 37% of subjects allocated to and remaining on diet therapy at six years (n=376). There was a significant decrease in beta-cell function from 1 to 6 years (p<0.0001). From these data, it can be seen that the decline of beta-cell function occurs many years before the diagnosis of diabetes. Beta cell function is thought to decline by 1% per year during normal ageing. Reference United Kingdom Prospective Diabetes Study Group (UKPDS 16). Diabetes. 1995; 44: 1249-1258. Diet-treated, n=376 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 Time from diagnosis (years) Adapted from UKPDS 16. Diabetes. 1995; 44: 1249-1258

Beta-cell dysfunction in diabetes Insulin secretion in lean mouse Insulin secretion in diabetic mouse Lister CA et al. Diabetologia 1998; 41 (Suppl 1): A169. Abstract 660

Homeostasis Model Assessment (HOMA) Clamp technique measures under hyperinsulinaemic conditions1 – considered the ‘gold standard’ HOMA estimates insulin sensitivity and beta-cell function using fasting insulin and glucose2 from a single sample and correlates well with other insulin sensitivity tests Well correlated with other insulin sensitivity tests (eg intravenous glucose tolerance test) and beta-cell function tests (eg hyperglycaemic clamp) There is a feeling that the imprecision of the homeostasis model assessment (HOMA) limits its clinical application; however, the significant correlations of the HOMA estimates with independent measurements of insulin resistance support the theoretical background of the analysis.1 Interestingly, a small study (n=63) by Lansang MC et al compared the euglycaemic clamp and the HOMA in patients with and without hypertension. It was concluded that the HOMA can be used reliably for measuring insulin resistance in hypertension.2 References 1. Matthews DR. Diabetologia 1985; 28: 412-419. 2. Lansang MC et al. Am J Hypertens 2001; 14: 51-53. 1. DeFronzo RA et al. Am J Physiol 1979; 237: E214-E223 2. Matthews DR et al. Diabetologia 1985; 28: 412-419

Homeostasis Model Assessment (HOMA) Normal: 100% beta-cell function: insulin resistance (R) = 1 20  insulin* (mU/ml) glucose* (mmol/l) - 3.5 Beta-cell function (%) = insulin* (mU/ml)  glucose* (mmol/l) 22.5 Insulin resistance = The model computes values from fasting insulin and glucose measurements. In homeostasis, with 100% beta-cell function, normal insulin resistance is assigned a value of 1. The percentage of beta-cell function is determined by the following equation: 20  fasting insulin level [µU/ml]  FPG level [mmol/l] - 3.5 The degree of insulin resistance is calculated by multiplying fasting insulin (µU/ml) by FPG (mmol/l) and dividing by 22.5. *fasting levels Haffner S. Diabetes Care 1996; 19: 1139

Homeostasis Model Assessment (HOMA) 50 40 30 20 10 b=200% Decreasing b-cell function (b) b=100% Increasing insulin resistance (R) R=16 Basal plasma insulin (mU/ml) b=50% R=8 b=25% This graphic representation of HOMA shows the model prediction of steady-state plasma glucose and insulin concentrations for a series of different beta-cell functions (red) and insulin resistance values (yellow). For any individual, FPG and fasting insulin may be entered on the grid, and the estimated beta-cell function and insulin resistance may be obtained. R=2 R=4 R=1 R=2 R=½ 2 4 6 8 10 12 14 Basal plasma glucose (mmol/l) Matthews et al. Diabetologia 1985; 28: 412