Lifestyle and glycaemic control before and after the onset of type 2 diabetes

Summary, in English

Type 2 diabetes (T2D) is a complex disease with widespread physiological insults to the regulation of metabolic homeostasis, above all glycaemic regulation. The pathogenesis of T2D and its progression is broadly understood to be through a gradual decrease in peripheral insulin sensitivity, a compensatory rise in insulin secretion, and a gradual decline in beta-cell function, resulting in glycaemic dysregulation and eventual T2D. Unhealthful lifestyle factors such as low physical activity (PA), energy dense diets with poor nutritional value, and chronic positive calorie balance are associated with an accelerated decline in glycaemic control and obesity. Single nucleotide polymorphisms (SNPs) discovered in genome wide association studies (GWAS) have demonstrated a genetic susceptibility to T2D (65 SNPs), fasting glucose (36 SNPs), 2-hr glucose (9 SNPs), and obesity (97 SNPs).
In Paper 1, in 3,444 adults in northern Sweden, we compared the predictive ability of lifestyle factors and the aforementioned SNPs with T2D and obesity for incidence of T2D, impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and obesity over ~10 years. We found that lifestyle and genetic factors had broadly the same predictive ability (by ROC AUC) for incidence in T2D (75% vs. 74%), IFG (63% vs. 66%), IGT (64% vs. 61%) and obesity (68% vs. 73%). With exception of IGT, adding genetic factors to lifestyle models improved predictive ability with resulting continuous net reclassification improvements of 58%, 36% and, 64% for T2D, IFG and obesity, respectively.
In paper 2 and 3, we overview the rationale, design and baseline results from two new prospective cohort studies within the DIRECT (Diabetes Research into Patient Stratification) Consortium. These cohort studies aim to improve prevention and treatment of T2D by discovering new biomarkers for glycaemic deterioration before (Cohort 1, N =2,335) and after the onset of T2D (Cohort 2, N =830). The cohorts are comprehensively assessed at follow-up visits at 18, 36 (Cohort 2) and 48 (Cohort 1) months. Aside from standard measurements, clinical assessments include: Beta-cell function, insulin sensitivity, glycaemia, objective PA, diet, abdominal MRI, genomic, transcriptomic, metabolomic, proteomic and microbiomic assessments.
A potential mechanism behind the pathogenesis of T2D has been hypothesised in a ‘twin-cycle’ model. In the first ‘liver cycle’, peripheral insulin resistance, in combination with a positive caloric balance, leads to accumulating liver fat. The hyperinsulinaemia from insulin resistance leads to an increase in hepatic de-novo lipogenesis, further increasing liver fat. This leads to reduced insulin-mediated suppression of gluconeogenesis, further increasing glycaemia, insulinaemia and accelerating the liver cycle. The increased very low lipoprotein secretion from lipogenesis eventually increases ectopic triglycerides in surrounding tissue, such as the pancreas. This feeds a ‘pancreatic cycle’ where lipotoxicity and glucotoxicity reduces beta-cell function and postprandial glucose, further accelerating the liver-cycle.
In paper 4, I test the ‘twin-cycle’ hypothesis and if the association between PA and glycaemic control is mediated by parameters within the model. Using structural equation modelling in newly gathered DIRECT baseline dataset, I find that: most of the relationships in the ‘twin-cycle’ hypothesis are observed as hypothesised in both prediabetes and T2D; that PA is associated with most parameters in the model; and, that the association of PA with glycaemic control and liver fat is mostly mediated by whole body insulin sensitivity.