In 2021, the Centers for Disease Control and Prevention estimated that 49 percent of the U.S. population had either prediabetes or type 2 diabetes. And, of those diagnosed with type 2 diabetes, more than 90 percent are overweight or obese.1
The striking overlap between type 2 diabetes and obesity reflects the convergence in the underlying pathophysiology of these conditions – so much so, in fact, that the term “diabesity” was coined to describe diabetes in the context of obesity. As recognition of the overlap between obesity and diabetes has grown, so have efforts to develop treatments that can treat the two conditions in tandem.
Type 2 diabetes is characterised by abnormally high blood sugar (glucose) levels due to a combination of insulin resistance – in which cells become less responsive to insulin signals – and impaired insulin secretion by pancreatic beta cells. Together, insulin resistance and insufficient insulin secretion result in a profound dysregulation of insulin-mediated processes, which maintain steady levels of metabolic fuel in the blood, despite discrete intervals of consumption and fasting.2
Specifically, insulin mediates mechanisms for lowering the levels of circulating glucose, free fatty acids and amino acids, while promoting their synthesis and storage as glycogen, lipids and proteins respectively. For instance, insulin, released by the pancreas in response to elevated blood glucose levels, promotes the transport of glucose into the cells of the liver and skeletal muscle, and its synthesis into glycogen, so that it can be stored. Meanwhile, it inhibits the degradation of glycogen and the release of glucose back into the bloodstream.2
Mounting evidence suggests that, in most instances, the insulin resistance that precedes type 2 diabetes is obesity related. Obesity-related insulin resistance explains why weight loss can improve and sometimes normalize insulin sensitivity in obese patients with type 2 diabetes.3
However, more than 70 percent of the obese population is insulin resistant, and only a subset of these patients will develop type 2 diabetes.4 The reason why some of these patients develop diabetes while others do not may be explained in part by genetic factors, such as those that may contribute to the impairment of pancreatic beta cells.5
That said, many of the molecular mechanisms for obesity-driven insulin resistance also contribute to the impairment of pancreatic beta cells. A number of these proposed mechanisms are now supported by the successful development of therapeutic interventions that treat obesity and diabetes.
For example, one well-established factor in obesity-driven insulin resistance is chronically elevated levels of free fatty acids (FFAs).6 Overabundant adipose tissue releases high levels of FFAs into the blood, which are then deposited in other tissues. These deposits may blunt insulin signaling in muscle and liver cells, and contribute to the loss of pancreatic beta-cells. As a result, drugs targeting FFA receptors are in development for the treatment of obesity and type 2 diabetes.7
Obesity-driven changes in the endocrine activity observed in adipose tissue and in the gastrointestinal tract may also drive insulin resistance and reduced insulin secretion. For instance, the amount or effect of a gut-derived hormone, glucagon-like peptide-1 (GLP-1), can be reduced in obese patients.6 GLP-1 increases insulin secretion by the pancreas, and also increases feelings of satiety. Therefore, an obesity-driven reduction in, or reduced sensitivity to, GLP-1 contributes to insulin insufficiencies that underlie type 2 diabetes. This has made GLP-1 an ideal therapeutic target for both conditions, as evidenced by the efficacy of GLP-1 receptor agonist-based medications and bariatric surgery.
By binding to GLP-1 receptors, GLP-1 receptor agonists promote insulin secretion and synthesis, slow gastric emptying and reduced appetite.6 Meanwhile, post-bariatric surgery changes include large increases in GLP-1, along with other gut-derived hormones involved in satiety and blood-sugar regulation. In addition, changes in the gut microbiome after surgery alter the absorption of nutrients. Many of these changes occur so rapidly that patients ostensibly receiving an obesity treatment return home from the hospital without the need for diabetes medications.8
Along with identifying promising therapeutic targets, an improved understanding of the mechanisms underlying obesity and diabetes provide insight into why some patients respond poorly to treating diabetes in isolation. For example, several classes of anti-diabetic medications, including insulins, effectively address insulin deficiency, but are associated with the risk of weight gain. These treatments may be suboptimal for some diabetic patients with obesity-driven insulin resistance.9
Meanwhile, certain treatments –- such as GLP-1 receptor agonists –- which address the underlying pathophysiology shared by diabetes and obesity, are receiving well-deserved attention, and are shifting development pathways for drugs that have the potential to treat both conditions. Historically, asset development – including the development of GLP-1 receptor agonists – proceeded from diabetes to weight loss indications. However, there is now increased interest in the simultaneous development of assets for diabetes and obesity as we recognise the need to address the growing incidence of obesity and diabetes in tandem.
Contact us to learn how we can help support your clinical trials for endocrine & metabolic disorders including diabestes and obesity.
References
1. National Diabetes Statistics Report | Diabetes | CDC. Published November 29, 2023. Accessed December 13, 2023. https://www.cdc.gov/diabetes/data/statistics-report/index.html
2. Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001;414(6865):799-806. doi:10.1038/414799a
3. Gerich JE. Insulin Resistance Is Not Necessarily an Essential Component of Type 2 Diabetes1. J Clin Endocrinol Metab. 2000;85(6):2113-2115. doi:10.1210/jcem.85.6.6646
4. Calori G, Lattuada G, Piemonti L, et al. Prevalence, Metabolic Features, and Prognosis of Metabolically Healthy Obese Italian Individuals. Diabetes Care. 2011;34(1):210-215. doi:10.2337/dc10-0665
5. Walker JT, Saunders DC, Rai V, et al. Genetic risk converges on regulatory networks mediating early type 2 diabetes. Nature. Published online December 4, 2023:1-9. doi:10.1038/s41586-023-06693-2
6. Ruze R, Liu T, Zou X, et al. Obesity and type 2 diabetes mellitus: connections in epidemiology, pathogenesis, and treatments. Front Endocrinol. 2023;14. Accessed September 22, 2023. https://www.frontiersin.org/articles/10.3389/fendo.2023.1161521
7. Ichimura A, Hasegawa S, Kasubuchi M, Kimura I. Free fatty acid receptors as therapeutic targets for the treatment of diabetes. Front Pharmacol. 2014;5:236. doi:10.3389/fphar.2014.00236
8. Conte C, Lapeyre-Mestre M, Hanaire H, Ritz P. Diabetes Remission and Relapse After Bariatric Surgery: a Nationwide Population-Based Study. Obes Surg. 2020;30(12):4810-4820. doi:10.1007/s11695-020-04924-3
9. Hanefeld M, Fleischmann H, Siegmund T, Seufert J. Rationale for Timely Insulin Therapy in Type 2 Diabetes Within the Framework of Individualised Treatment: 2020 Update. Diabetes Ther. 2020;11(8):1645-1666. doi:10.1007/s13300-020-00855-5
In this section
-
Digital Disruption
- AI and clinical trials
-
Clinical trial data anonymisation and data sharing
-
Clinical Trial Tokenisation
-
Closing the evidence gap: The value of digital health technologies in supporting drug reimbursement decisions
-
Digital disruption in biopharma
-
Disruptive Innovation
- Remote Patient Monitoring
-
Personalising Digital Health
- Real World Data
-
The triad of trust: Navigating real-world healthcare data integration
-
Patient Centricity
-
Agile Clinical Monitoring
-
Capturing the voice of the patient in clinical trials
-
Charting the Managed Access Program Landscape
-
Developing Nurse-Centric Medical Communications
- Diversity and inclusion in clinical trials
-
Exploring the patient perspective from different angles
-
Patient safety and pharmacovigilance
-
A guide to safety data migrations
-
Taking safety reporting to the next level with automation
-
Outsourced Pharmacovigilance Affiliate Solution
-
The evolution of the Pharmacovigilance System Master File: Benefits, challenges, and opportunities
-
Sponsor and CRO pharmacovigilance and safety alliances
-
Understanding the Periodic Benefit-Risk Evaluation Report
-
A guide to safety data migrations
-
Patient voice survey
-
Patient Voice Survey - Decentralised and Hybrid Trials
-
Reimagining Patient-Centricity with the Internet of Medical Things (IoMT)
-
Using longitudinal qualitative research to capture the patient voice
-
Agile Clinical Monitoring
-
Regulatory Intelligence
-
An innovative approach to rare disease clinical development
- EU Clinical Trials Regulation
-
Using innovative tools and lean writing processes to accelerate regulatory document writing
-
Current overview of data sharing within clinical trial transparency
-
Global Agency Meetings: A collaborative approach to drug development
-
Keeping the end in mind: key considerations for creating plain language summaries
-
Navigating orphan drug development from early phase to marketing authorisation
-
Procedural and regulatory know-how for China biotechs in the EU
-
RACE for Children Act
-
Early engagement and regulatory considerations for biotech
-
Regulatory Intelligence Newsletter
-
Requirements & strategy considerations within clinical trial transparency
-
Spotlight on regulatory reforms in China
-
Transfer of marketing authorisation
-
An innovative approach to rare disease clinical development
-
Therapeutics insights
- Endocrine and Metabolic Disorders
- Cardiovascular
- Cell and Gene Therapies
- Central Nervous System
-
Glycomics
- Infectious Diseases
- NASH
-
Oncology
- Paediatrics
-
Respiratory
-
Rare and orphan diseases
-
Advanced therapies for rare diseases
-
Cross-border enrollment of rare disease patients
-
Crossing the finish line: Why effective participation support strategy is critical to trial efficiency and success in rare diseases
-
Diversity, equity and inclusion in rare disease clinical trials
-
Identify and mitigate risks to rare disease clinical programmes
-
Leveraging historical data for use in rare disease trials
-
Natural history studies to improve drug development in rare diseases
-
Patient Centricity in Orphan Drug Development
-
The key to remarkable rare disease registries
-
Advanced therapies for rare diseases
-
Transforming Trials
-
Accelerating biotech innovation from discovery to commercialisation
-
Ensuring the validity of clinical outcomes assessment (COA) data: The value of rater training
-
Linguistic validation of Clinical Outcomes Assessments
-
Optimising biotech funding
- Adaptive clinical trials
-
Best practices to increase engagement with medical and scientific poster content
-
Decentralised clinical trials
-
Biopharma perspective: the promise of decentralised models and diversity in clinical trials
-
Decentralised and Hybrid clinical trials
-
Practical considerations in transitioning to hybrid or decentralised clinical trials
-
Navigating the regulatory labyrinth of technology in decentralised clinical trials
-
Biopharma perspective: the promise of decentralised models and diversity in clinical trials
-
eCOA implementation
- Flexible delivery models
-
Implications of COVID-19 on statistical design and analyses of clinical studies
-
Improving pharma R&D efficiency
-
Increasing Complexity and Declining ROI in Drug Development
-
Innovation in Clinical Trial Methodologies
- Partnership insights
-
Risk Based Quality Management
-
Transforming the R&D Model to Sustain Growth
-
Accelerating biotech innovation from discovery to commercialisation
-
Value Based Healthcare
-
Strategies for commercialising oncology treatments for young adults
-
US payers and PROs
-
Accelerated early clinical manufacturing
-
Cardiovascular Medical Devices
-
CMS Part D Price Negotiations: Is your drug on the list?
-
COVID-19 navigating global market access
-
Ensuring scientific rigor in external control arms
-
Evidence Synthesis: A solution to sparse evidence, heterogeneous studies, and disconnected networks
-
Global Outcomes Benchmarking
-
Health technology assessment
-
Perspectives from US payers
-
ICER’s impact on payer decision making
-
Making Sense of the Biosimilars Market
-
Medical communications in early phase product development
-
Navigating the Challenges and Opportunities of Value Based Healthcare
-
Payer Reliance on ICER and Perceptions on Value Based Pricing
-
Payers Perspectives on Digital Therapeutics
-
Precision Medicine
-
RWE Generation Cross Sectional Studies and Medical Chart Review
-
Survey results: How to engage healthcare decision-makers
-
The affordability hurdle for gene therapies
-
The Role of ICER as an HTA Organisation
-
Strategies for commercialising oncology treatments for young adults
-
Blog
-
Videos
-
Webinar Channel