Defining the insulin signalling defects in insulin resistance and type 2 diabetes mellitus

Abstract

Insulin resistance is central to type 2 diabetes, and its relationships to adiposity are complex. Some obese humans are protected from insulin resistance and the Metabolic Syndrome. By studying these individuals we attempt to identify factors protective against insulin resistance, distinguishing between insulin resistance, hyperglycaemia, and adiposity per se. We recruited 81 individuals, in 4 groups: lean control (n=23, BMI ≤ 25 kg/m2, HOMA<2), Obresistant (n=21, BMI>25 kg/m2, HOMA>3), T2D (n=21), and Obsensitive (n=16, BMI>25 kg/m2, HOMA<1.5). Obresistant, T2D and Obsensitive were matched for waist:hip ratio, total body fat %, central fat %, fat content of legs (kg) and average subcutaneous fat cm2. Obsensitive were as insulin-sensitive as the lean by HOMA (1.2±0.3 vs 1.2±0.4, respectively) and hyperinsulinaemic-euglycaemic clamp (GIR 86±36 vs 92±23 μmol/min/kg FFM, respectively) despite twice their total and central fat. Obresistant and T2D had significantly lower GIR/FFM (61±24 vs 44±13 µmol/min/kgFFM, respectively). Chapter 3 demonstrates that adiponectin and FGF21 levels, as well as visceral and hepatic fat, are strong predictors of insulin resistance in human muscle. Chapter 4 shows that pAkt is lower in Obresistance and T2D, but pAS160 (downstream of pAkt) is lower in all overweight/obese groups, indicating that adiposity may influence insulin signalling-mediated insulin resistance. Adiponectin strongly mirrors pAkt, and FABP4 correlates with pAS160. Chapter 5 shows that urinary catecholamines correlate to fat mass rather than insulin sensitivity. Obesity may lead to higher sympathetic drive, with compensatory parasympathetic drive lost in Obresistant (maintained in Obsensitive). Once T2D develops sympathetic drive is also blunted. Chapter 6 demonstrates that plasma and muscle ceramides are associated with insulin resistance and visceral adiposity. There were negative associations between ceramides and insulin-stimulated pAkt309, and baseline adiponectin; and positive associations with FGF21, FABP4 and LCN2. A number of pathways may augment insulin sensitivity: THC 24:1, 24:0 and 22:0 negatively associate with deep subcutaneous and hepatic adiposity in women; GM3 22:0 and SM 33:1 through (superficial) subcutaneous fat; and SM 32:2 through lower deep subcutaneous fat and FABP4. No previous study has definitively demonstrated insulin-sensitivity at a molecular level in muscle of Obsensitive humans. Their study raises potential diagnostic or therapeutic avenues.