In Aim 1 we enrolled participants with type-2 diabetes and features of Severe Insulin-Deficient Diabetes (SIDD) or Severe Insulin-Resistant Diabetes (SIRD), representing subgroups with different pathophysiology and increased risk for complications. Participants were randomly assigned to the GLP-1-receptor agonist semaglutide or the SGLT2-inhibitor dapagliflozin during six months. Semaglutide induced a larger reduction of HbA1c than dapagliflozin with a pronounced effect in SIDD. We also found that continuous measures of BMI, blood pressure, insulin secretion and insulin resistance can be used to identify those who will likely have the largest improvement of glycemic control and cardiovascular risk factors by adding semaglutide or dapagliflozin.
Moreover, we have analyzed further hormonal data, particularly glucagon and somatostatin, from these patients. Glucagon and somatostatin are central metabolic hormones, but their role in determining treatment response has been unknown. Interestingly, we found that fasting glucagon and somatostatin determines the response to GLP1ra and SGLT2i. Patients with low fasting glucagon and somatostatin had pronounced response to GLP1ra and patients with high fasting glucagon and somatostatin had the best response to SGLT2i. This opens a previously unrecognized opportunity to identify those who will benefit most from GLP1ra and SGLT2i.
In Aim 2 we set up a methodology to study beta-cell function and gene expression on the single-cell level. The direct coupling between physiology and gene expression enables us to determine the heterogeneous changes of beta-cell function during the development of type 2 diabetes in an unprecedented manner. By directly correlating function and gene expression at the single-cell level we have identified pools of low- and high-functioning beta-cells with distinct gene expression and a surprisingly inverse pattern in type 2 diabetes. The high-functioning cells in normal condition are characterized by high expression of genes involved in mitochondrial metabolism. In type 2 diabetes, these cells become, however, the least functioning cells, suggesting that the high mitochondrial metabolism makes them more vulnerable to diabetic conditions. We have also verified this new pathophysiological hypothesis experimentally by increasing mitochondrial metabolism by BCH and found that BCH-treated cells have increased insulin secretion in normal conditions but get particularly impaired when cultured in diabetes-like conditions with high glucose and palmitate. And when we in an opposite manner reduce mitochondrial metabolism by mannoheptulose, the cells perform poorer in normal conditions but are spared when cultured in diabetes-like conditions. This is yet a largely unexplored area, and the results are expected to benefit a range of researchers by addressing critical knowledge gaps and facilitate more specific drug development.
We have in Aim 3 conducted a randomized trial of individuals with impaired fasting glucose and found that sulforaphane-containing broccoli sprout extract (BSE) significantly reduced fasting blood glucose compared with placebo. Furthermore, a data-driven cluster analysis identified three pathophysiological subgroups of impaired fasting glucose. Individuals of the largest subgroup, characterized by mild obesity, low insulin resistance and reduced insulin secretion, had a pronounced treatment response. Gut microbiota analyses showed that responders had a higher abundance of a Bacteroides-encoded transcriptional regulator required for the conversion of the inactive precursor to bioactive sulforaphane. The abundance of this gene operon correlated with sulforaphane serum concentration. These findings suggest a new model for how the host pathophysiology and gut microbiota interact to influence metabolic treatment response that may have broad implications. The findings suggest that sulforaphane-containing BSE could provide a new modality for early anti-hyperglycemic intervention and represent a first step towards precision treatment of prediabetes based on the individual pathophysiology.
