Periodic Reporting for period 3 - TRANSLATIONAL (A new translational strategy for tailored treatment of type 2 diabetes)
Période du rapport: 2023-10-01 au 2025-03-31
Over 300 million people have type 2 diabetes, and the number is expected to exceed half a billion by 2030. Current treatment strategies fail to stop the progressive course of the disease. As a consequence, the disease causes severe complications in the kidneys, eyes and the cardiovascular system, making type 2 diabetes one of the greatest threats to human health.
Clinical guidelines recommend metformin as initial therapy to all patients but emphasise the need for subsequent personalized treatment with additional drugs. Although this sounds attractive, it is currently implemented on trial-and-error fashion and the concept as such has in fact not been examined systematically.
An analysis in 2018 of 9,000 diabetic patients highlighted four clusters of type 2 diabetes patients, each with different characteristics and risk of complications. Two of these clusters are particularly aggressive: one has been coined SIDD (Severe Insulin-Deficient Diabetes) and features low age at onset, low body mass index and poor secretion of the glucose-lowering hormone insulin; the other, termed SIRD (Severe Insulin-Resistant Diabetes), presents at higher age and associates with high body mass index and high resistance to insulin in muscle, liver and fat.
This sheds new light on the mounting problem of type 2 diabetes by emphasising the high variability of the pathophysiology and providing a new tool to distinguish individuals at different ends of the pathophysiological spectrum. Importantly, it leads us to propose that anti-diabetic treatment should ideally target the underlying pathophysiology of each individual patient.
The overarching goal of TRANSLATIONAL is to test this proposition, both by the use of existing drugs and by investigating previously unexplored avenues to enable more precise interventions guided by the disease mechanisms.
The objectives are to
1) test the effect of existing anti-diabetic drugs in patients with different disease characteristics;
2) determine the functional and gene expression changes that cause impaired insulin secretion; and
3) investigate the effects and mechanisms of action of new potential anti-diabetic compounds.
The combined experimental and clinical studies of this research program have the potential to open up new ways for managing type 2 diabetes and enabling more specific therapy. The proposed research focuses on the two most severe forms of the newly identified subtypes of type 2 diabetes. It is expected to lead to improved understanding of impaired insulin secretion and how to treat it, in the near term by more precise use of existing anti-diabetic drugs, and in the long term potentially via new compounds targeting the underlying disease mechanism.
We will also study sulforaphane, which could be an attractive new treatment option for for several reasons. First, it improves glucose tolerance. Second, it has few side effects as suggested from previous studies on cancer prevention and our own recent study. Third, it can be provided as a functional food, which may be particularly attractive for early intervention.
Clinical guidelines recommend metformin as initial therapy to all patients but emphasise the need for subsequent personalized treatment with additional drugs. Although this sounds attractive, it is currently implemented on trial-and-error fashion and the concept as such has in fact not been examined systematically.
An analysis in 2018 of 9,000 diabetic patients highlighted four clusters of type 2 diabetes patients, each with different characteristics and risk of complications. Two of these clusters are particularly aggressive: one has been coined SIDD (Severe Insulin-Deficient Diabetes) and features low age at onset, low body mass index and poor secretion of the glucose-lowering hormone insulin; the other, termed SIRD (Severe Insulin-Resistant Diabetes), presents at higher age and associates with high body mass index and high resistance to insulin in muscle, liver and fat.
This sheds new light on the mounting problem of type 2 diabetes by emphasising the high variability of the pathophysiology and providing a new tool to distinguish individuals at different ends of the pathophysiological spectrum. Importantly, it leads us to propose that anti-diabetic treatment should ideally target the underlying pathophysiology of each individual patient.
The overarching goal of TRANSLATIONAL is to test this proposition, both by the use of existing drugs and by investigating previously unexplored avenues to enable more precise interventions guided by the disease mechanisms.
The objectives are to
1) test the effect of existing anti-diabetic drugs in patients with different disease characteristics;
2) determine the functional and gene expression changes that cause impaired insulin secretion; and
3) investigate the effects and mechanisms of action of new potential anti-diabetic compounds.
The combined experimental and clinical studies of this research program have the potential to open up new ways for managing type 2 diabetes and enabling more specific therapy. The proposed research focuses on the two most severe forms of the newly identified subtypes of type 2 diabetes. It is expected to lead to improved understanding of impaired insulin secretion and how to treat it, in the near term by more precise use of existing anti-diabetic drugs, and in the long term potentially via new compounds targeting the underlying disease mechanism.
We will also study sulforaphane, which could be an attractive new treatment option for for several reasons. First, it improves glucose tolerance. Second, it has few side effects as suggested from previous studies on cancer prevention and our own recent study. Third, it can be provided as a functional food, which may be particularly attractive for early intervention.
Attempts have been made to classify diabetes into subgroups based on clinical variables or genetics, but the relevance of such stratification in predicting treatment response is unknown. Glucagon-like peptide-1 receptor agonists (GLP1ra) and sodium-glucose transporter-2 inhibitors (SGLT2i) are two anti-diabetic drugs that are increasingly used in addition to metformin, as they have shown cardiovascular benefits in patients with established cardiovascular disease, heart failure or chronic kidney disease. This encompasses, however, only ~20% of patients with type 2 diabetes. Thus, for the majority of patients it is unclear who will benefit most from these common drugs. Moreover, choice of treatment is rarely based on measurements of the disease characteristics that drive the deteriorating metabolic state that ultimately leads to cardiovascular complications.
In goal one of this programme we have conducted a randomized clinical trial to test the effect of GLP1ra and SGLT2i in patients with different disease characteristics. The usefulness of stratifying patients into subgroups with poor insulin secretion and high insulin resistance, respectively, was evaluated and contrasted with an approach based on continuous pathophysiological variables. We found a set of variables that can be easily obtained in addition to glucose to identify those who will likely have insufficient effect of metformin and the largest change in glycaemic control, body mass index and systolic blood pressure in response to GLP1ra or SGLT2i. The results also demonstrate that continuous pathophysiological variables provide more information on treatment response to GLP1ra and SGLT2i drugs than stratifying patients into subgroups. The findings could facilitate more informed use of these common drugs, which is important in view of their side effects and costs and the high number of patients who do not reach glycaemic targets.
Although existing drugs reduce hyperglycaemia, they fail to stop the gradual failure of insulin-producing beta-cells in the pancreas that is the key determinant of disease progression. To better understand how to preserve the beta-cells and identify new therapeutic targets, we have in goal two of TRANSLATIONAL set up a methodology to study beta-cell function compared with gene expression analysis on the single-cell level. The direct coupling, on the single-cell level, 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. 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.
The methodology has been refined in the last two years in our lab to ensure consistent identification of cells with different secretory performance. We have currently sequenced cells from non-diabetic (C57BL/6) mice, from fumarate hydratase knockout mice (with mild diabetes because of impaired mitochondrial metabolism) and from db/db mice (with severe obesity-induced diabetes). Furthermore, cells from both non-diabetic and diabetic human donors have been sequenced. A number of genes with consistent expression patterns have been selected for further mechanistic studies. Some of these genes are known markers of beta-cell maturity and function, while others encode transcription factors, metabolic enzymes and receptors that have not been picked up in previous whole-islet expression analyses or single-cell expression studies without concomitant functional data.
There is a need for new early interventions in prediabetes (the stage before overt diabetes) and improved understanding of the heterogeneity of treatment response to counteract the escalating global increase of type 2 diabetes. Sulforaphane is an isothiocyanate compound that reduces hepatic glucose production and is well tolerated when provided as a broccoli sprout extract (BSE). We have in goal three of TRANSLATIONAL conducted a randomized trial of individuals with impaired fasting glucose and found that 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. They had also a distinct gut microbiota composition with low gene richness but high butyrate production potential. 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.
In goal one of this programme we have conducted a randomized clinical trial to test the effect of GLP1ra and SGLT2i in patients with different disease characteristics. The usefulness of stratifying patients into subgroups with poor insulin secretion and high insulin resistance, respectively, was evaluated and contrasted with an approach based on continuous pathophysiological variables. We found a set of variables that can be easily obtained in addition to glucose to identify those who will likely have insufficient effect of metformin and the largest change in glycaemic control, body mass index and systolic blood pressure in response to GLP1ra or SGLT2i. The results also demonstrate that continuous pathophysiological variables provide more information on treatment response to GLP1ra and SGLT2i drugs than stratifying patients into subgroups. The findings could facilitate more informed use of these common drugs, which is important in view of their side effects and costs and the high number of patients who do not reach glycaemic targets.
Although existing drugs reduce hyperglycaemia, they fail to stop the gradual failure of insulin-producing beta-cells in the pancreas that is the key determinant of disease progression. To better understand how to preserve the beta-cells and identify new therapeutic targets, we have in goal two of TRANSLATIONAL set up a methodology to study beta-cell function compared with gene expression analysis on the single-cell level. The direct coupling, on the single-cell level, 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. 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.
The methodology has been refined in the last two years in our lab to ensure consistent identification of cells with different secretory performance. We have currently sequenced cells from non-diabetic (C57BL/6) mice, from fumarate hydratase knockout mice (with mild diabetes because of impaired mitochondrial metabolism) and from db/db mice (with severe obesity-induced diabetes). Furthermore, cells from both non-diabetic and diabetic human donors have been sequenced. A number of genes with consistent expression patterns have been selected for further mechanistic studies. Some of these genes are known markers of beta-cell maturity and function, while others encode transcription factors, metabolic enzymes and receptors that have not been picked up in previous whole-islet expression analyses or single-cell expression studies without concomitant functional data.
There is a need for new early interventions in prediabetes (the stage before overt diabetes) and improved understanding of the heterogeneity of treatment response to counteract the escalating global increase of type 2 diabetes. Sulforaphane is an isothiocyanate compound that reduces hepatic glucose production and is well tolerated when provided as a broccoli sprout extract (BSE). We have in goal three of TRANSLATIONAL conducted a randomized trial of individuals with impaired fasting glucose and found that 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. They had also a distinct gut microbiota composition with low gene richness but high butyrate production potential. 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.
The completed study in goal one is the first trial that tests the concept of personalized treatment of patients with different pathophysiological characteristics. This is an advantage as compared with previous observational studies or metaanalyses, where confounders are more difficult to control for. The trial investigates both GLP1ra and SGLT2i drugs in the same randomized setting, which has not previously been done. The results of this trial are of clinical relevance, as they highlight specific disease variables that can be used in clinical routine to identify those who will respond most favourably to these drugs in terms of HbA1c, BMI and systolic blood pressure. This would add important information and a fuller picture of the overall effects in addition to considerations based on cardiorenal comorbidities. Since these drugs are expensive, this is particularly important in settings of resource constraints.
The comprehensive characterization of the functional and gene expression changes in type 2 diabetes will be followed by mechanistic investigations of the most interesting genes. We will use a translational workflow proceeding from cellular experiments to animal and clinical studies that we have advanced during the last decade to successfully identify new disease mechanisms and pharmacological means. By defining the phenotype and cellular pools of -cells in a more precise manner than has previously been possible, the results are expected to benefit both academic and industrial researchers by stimulating new research questions and previously unexplored avenues in precision medicine.
The results of the third study extend on previous research on the treatment of prediabetes in three main ways. First, the trial shows that sulforaphane-containing BSE reduces fasting blood glucose in individuals with impaired fasting glucose. Second, the data reveal marked variations in clinical characteristics and treatment response in different subgroups, which highlights the need to personalize interventions in prediabetes. Third, the study shows that the gut microbiota composition differs between the subgroups and is associated with the anti-hyperglycemic response.
BSE may be an interesting addition to the therapeutic arsenal for several reasons. It reduces fasting blood glucose by a similar magnitude to that observed by metformin. Moreover, data from this trial as well as long-term studies on cancer prevention show that BSE has few adverse effects. This is important in prediabetes, where tolerance for side effects is presumably lower. The provision as a BSE rather than a traditional drug might also be attractive to individuals with impaired fasting glucose, who do not necessarily view themselves as being ill.
The comprehensive characterization of the functional and gene expression changes in type 2 diabetes will be followed by mechanistic investigations of the most interesting genes. We will use a translational workflow proceeding from cellular experiments to animal and clinical studies that we have advanced during the last decade to successfully identify new disease mechanisms and pharmacological means. By defining the phenotype and cellular pools of -cells in a more precise manner than has previously been possible, the results are expected to benefit both academic and industrial researchers by stimulating new research questions and previously unexplored avenues in precision medicine.
The results of the third study extend on previous research on the treatment of prediabetes in three main ways. First, the trial shows that sulforaphane-containing BSE reduces fasting blood glucose in individuals with impaired fasting glucose. Second, the data reveal marked variations in clinical characteristics and treatment response in different subgroups, which highlights the need to personalize interventions in prediabetes. Third, the study shows that the gut microbiota composition differs between the subgroups and is associated with the anti-hyperglycemic response.
BSE may be an interesting addition to the therapeutic arsenal for several reasons. It reduces fasting blood glucose by a similar magnitude to that observed by metformin. Moreover, data from this trial as well as long-term studies on cancer prevention show that BSE has few adverse effects. This is important in prediabetes, where tolerance for side effects is presumably lower. The provision as a BSE rather than a traditional drug might also be attractive to individuals with impaired fasting glucose, who do not necessarily view themselves as being ill.