Clinical Context
The diabetic heart has fundamentally altered metabolism. Insulin resistance impairs cardiac glucose uptake, forcing the myocardium to rely almost exclusively on fatty acid oxidation. While fatty acids provide ATP, this metabolic inflexibility has consequences: fatty acid oxidation is less oxygen-efficient, generates reactive oxygen species, and produces lipotoxic intermediates that promote inflammation and fibrosis. The inability to switch to glucose during stress may contribute to diabetic cardiomyopathy.
Diastolic dysfunction is the earliest and most common cardiac abnormality in diabetes, often preceding systolic dysfunction by years. It manifests as impaired ventricular relaxation and filling, eventually contributing to heart failure with preserved ejection fraction (HFpEF). The metabolic inflexibility of the diabetic heart—its inability to efficiently utilize glucose—is increasingly recognized as a therapeutic target.
GLP-1 receptor agonists like exenatide have shown cardiovascular benefits beyond glucose lowering. Mechanistically, GLP-1 signaling may enhance myocardial glucose uptake, improve cardiac efficiency, and provide direct cardioprotection. Glucagon, paradoxically, also has positive inotropic effects and may synergize with GLP-1 agonism. This small mechanistic study tested whether exenatide-glucagon co-infusion could restore cardiac metabolic flexibility in diabetics.
Study Summary (PICO Framework)
Summary:
In adults with type 2 diabetes, exenatide + glucagon co-infusion significantly increased myocardial glucose uptake (~2-fold) and improved diastolic function compared to saline or glucagon alone, with no notable adverse effects.
| PICO | Description |
|---|---|
| Population | 8 adults with T2DM (age 52±12 years, BMI 31±4 kg/m²). |
| Intervention | Exenatide (50 ng/min load → 25 ng/min) + glucagon (12.5 ng/kg/min) co-infusion. |
| Comparison | Saline or glucagon alone. |
| Outcome | Myocardial glucose uptake: 9.2→20×10⁻³ µmol/g/min (P<0.05). Improved diastolic strain rate. No adverse effects. |
Clinical Pearls
1. The diabetic heart is “metabolically inflexible”—this study shows it can be rescued. Healthy hearts switch between glucose and fatty acids based on substrate availability and oxygen conditions. The diabetic heart loses this flexibility, stuck on fatty acid oxidation. The finding that exenatide-glucagon co-infusion doubled myocardial glucose uptake demonstrates that metabolic flexibility can be pharmacologically restored, at least acutely.
2. Glucagon’s cardiac effects are underappreciated. Glucagon is usually viewed only through the lens of glucose counterregulation. However, glucagon receptors are expressed in the heart, and glucagon has positive inotropic and chronotropic effects. The synergy with exenatide suggests that dual GLP-1/glucagon agonism (as in tirzepatide-related compounds or investigational agents) may have unique cardiac benefits.
3. Diastolic function improvement is particularly relevant for diabetic cardiomyopathy. Diastolic dysfunction is the hallmark of early diabetic heart disease and contributes to HFpEF—a condition with few effective therapies. Improving diastolic strain rate suggests that metabolic optimization could address this unmet need.
4. This is a small mechanistic study—proof of concept, not clinical practice. Eight patients, acute infusion, surrogate endpoints. This establishes biological plausibility for cardiac metabolic effects of GLP-1/glucagon agonism but doesn’t establish clinical benefit. It generates hypotheses for larger studies examining whether these acute metabolic changes translate to improved cardiac outcomes.
Practical Application
This study supports the cardiovascular rationale for GLP-1 receptor agonists: The cardiovascular outcome trials showing CV benefits with GLP-1 RAs (LEADER, SUSTAIN-6, REWIND, SELECT) have established clinical benefit. This mechanistic study provides one potential explanation: enhanced myocardial glucose utilization improving cardiac efficiency and function.
Watch emerging dual GLP-1/glucagon agonists: Several dual agonist compounds are in development. This study suggests they may have unique cardiac benefits beyond what single GLP-1 agonism provides. Tirzepatide (GLP-1/GIP dual agonist) has already shown impressive cardiovascular and metabolic effects; GLP-1/glucagon combinations may follow.
Consider diabetic cardiomyopathy as a metabolic disease: Traditional heart failure treatments focus on neurohormonal blockade. For diabetic patients, metabolic optimization—including glucose-lowering agents that improve cardiac substrate utilization—may be additionally important. GLP-1 RAs and SGLT2 inhibitors both have metabolic effects that may contribute to their cardiac benefits.
Don’t extrapolate acute infusion studies to chronic therapy: This study used continuous IV infusion of exenatide and glucagon—not representative of clinical GLP-1 RA use (subcutaneous injection, intermittent dosing). Whether chronic GLP-1 RA therapy produces sustained improvements in myocardial glucose uptake is unknown. The cardiovascular outcome trials provide the clinical evidence; this study provides mechanistic insight.
How This Study Fits Into the Broader Evidence
GLP-1 receptor agonists have established cardiovascular benefits in large outcome trials. LEADER (liraglutide), SUSTAIN-6 (semaglutide), and REWIND (dulaglutide) all showed significant reductions in major adverse cardiovascular events. The SELECT trial extended these benefits to patients with obesity without diabetes. The mechanisms underlying these benefits are multifactorial—weight loss, blood pressure reduction, lipid effects, and direct cardiac effects.
Myocardial metabolic imaging studies have shown that diabetic hearts have impaired glucose uptake and increased fatty acid utilization. Some studies suggest GLP-1 infusion acutely increases myocardial glucose uptake in humans, consistent with the findings here. Whether this translates to improved cardiac function and outcomes requires integration with clinical trial data.
The emerging GLP-1/glucagon dual agonist field builds on observations that glucagon has beneficial metabolic effects (increased energy expenditure, lipolysis) that complement GLP-1’s actions. This study suggests cardiac effects may be another dimension of dual agonism worth exploring.
Limitations to Consider
Very small sample size (n=8) limits statistical power and generalizability. Acute IV infusion doesn’t reflect chronic subcutaneous therapy. Surrogate endpoints (glucose uptake, strain rate) may not translate to clinical outcomes. No long-term follow-up. The combination studied (exenatide + glucagon) isn’t available as a combined product. Whether effects persist with chronic treatment is unknown.
Bottom Line
Exenatide and glucagon co-infusion approximately doubled myocardial glucose uptake and improved diastolic function markers in adults with type 2 diabetes compared to saline or glucagon alone. This small mechanistic study provides proof-of-concept that the metabolic inflexibility of the diabetic heart can be pharmacologically improved, offering mechanistic insight into why GLP-1 receptor agonists provide cardiovascular benefit. While not directly practice-changing, it supports prioritizing GLP-1 RAs in diabetic patients with or at risk for cardiac dysfunction and generates interest in emerging dual GLP-1/glucagon agonists.
Source: James Goodman, et al. “Exenatide and glucagon co-infusion increases myocardial glucose uptake and improves markers of diastolic dysfunction in adults with type 2 diabetes.” Read article here.
