Therapeutic Manipulation of Myocardial Metabolism Honka, Henri; Solis-Herrera, Carolina; Triplitt, Curtis ...
Journal of the American College of Cardiology,
04/2021, Letnik:
77, Številka:
16
Journal Article
Recenzirano
Odprti dostop
The mechanisms responsible for the positive and unexpected cardiovascular effects of sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists in patients with type 2 ...diabetes remain to be defined. It is likely that some of the beneficial cardiac effects of these antidiabetic drugs are mediated, in part, by altered myocardial metabolism. Common cardiometabolic disorders, including the metabolic (insulin resistance) syndrome and type 2 diabetes, are associated with altered substrate utilization and energy transduction by the myocardium, predisposing to the development of heart disease. Thus, the failing heart is characterized by a substrate shift toward glycolysis and ketone oxidation in an attempt to meet the high energetic demand of the constantly contracting heart. This review examines the metabolic pathways and clinical implications of myocardial substrate utilization in the normal heart and in cardiometabolic disorders, and discusses mechanisms by which antidiabetic drugs and metabolic interventions improve cardiac function in the failing heart.
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•Bioengineering of cardiac metabolism represents a novel strategy to improve cardiac function and slow the progression of myocardial disease.•Modification of myocardial metabolism by SGLT-2 inhibitors, GLP-1 RAs, and pioglitazone can reduce CV events in patients with type 2 diabetes.•The potential benefit of shifting fuel utilization pathways in patients with HF should be investigated in future trials.
Context:
Bariatric surgery leads to a rapid and sustained weight loss often accompanied with improvement in glucose homeostasis.
Objective:
The objective of this study was to investigate the effects ...of bariatric surgery on pancreatic lipid metabolism, blood flow, and glycemic control.
Design:
This was a longitudinal study.
Setting:
The study was conducted in a clinical research center.
Participants:
This study included 27 morbidly obese and 15 healthy control subjects.
Interventions:
Measurements were performed using positron emission tomography with the palmitate analog 14(R,S)-18Ffluoro-6-thia-heptadecanoic acid and radiowater (15OH2O) and computed tomography. In morbidly obese subjects, positron emission tomography/computed tomography imaging studies were performed before and 6 months after bariatric surgery (either Roux-en-Y gastric bypass or sleeve gastrectomy).
Main Outcome Measures:
Pancreatic fat and fat-free volume, fatty acid uptake and blood flow were measured as well as parameters of β-cell function, glucose tolerance, and insulin sensitivity.
Results:
Six months after bariatric surgery, 23% excess weight loss was observed (P < .0001), and diabetes remission was seen in 7 of 10 patients. When compared with preoperative values, after surgery, notable decreases in pancreatic fat volume (P < .01), fatty acid uptake, and blood flow (both P < .05) were seen, whereas no change was seen in pancreatic fat-free volume. The decrease in pancreatic fat volume and the preservation of blood flow were associated with favorable glucose homeostasis and β-cell function.
Conclusions:
Bariatric surgery elicits marked alterations in pancreatic lipid metabolism and blood flow, which may contribute to the observed improvement in glucose homeostasis and remission of type 2 diabetes.
OBJECTIVES/GOALS: In this study we sought to determine the role of glucagon-like peptide-1 (GLP-1), one of the main gut hormones in regulating glucose metabolism, after protein ingestion in patients ...with a history of Roux-en-Y gastric bypass (GB) and sleeve gastrectomy (SG). METHODS/STUDY POPULATION: We examined the glucose and islet-cell secretory responses to 50 g protein ingestion with and without a potent GLP-1 receptor antagonist, exendin-(9-39) Ex-9, in 10 GB-treated subjects, 9 SG-treated, and 7 non-operated controls (CN). The groups were matched for age, BMI, fat-free mass, fasting glucose and insulin, and HbA1c. The surgical groups also were matched for weight loss and time post-surgery. No subjects had diabetes. RESULTS/ANTICIPATED RESULTS: Protein ingestion resulted in an early rise in glycemia (AUCGlucose1hr) in GB and SG, whereas CN had minimal change in glucose (p<0.05). Protein ingestion enhanced C-peptide responses in all groups, but to a larger extent in GB and SG when compared to CN (p<0.05). Early glucagon response to protein ingestion (AUCGlucagon1hr) tended to be larger in GB and SG subjects when compared to CN (p=0.07). Ex-9 increased premeal and prandial glycemia in all groups (p<0.05), but increase in early glycemia (AUCGlucose1hr) was most notable in GB (p=0.1, interaction). This glycemic effect of Ex-9 was associated with a ~25% reduction in prandial C-peptide secretion in GB and SG and ~8% increase in CN (p<0.05, interaction). Early prandial glucagon responses were larger during studies with Ex-9 compared to those without (p<0.05). DISCUSSION/SIGNIFICANCE: Our findings indicate that glucose metabolism after protein ingestion is altered after GB and SG. To our knowledge, this is the first report to demonstrate that endogenous GLP-1 contributes to glucose and islet-cell secretory response to protein ingestion, and that GB and SG exaggerate GLP-1 contribution to insulin secretion after protein ingestion.
Objective Meal ingestion is followed by a redistribution of blood flow (BF) within the splanchnic region contributing to nutrient absorption, insulin secretion and glucose disposal, but factors ...regulating this phenomenon in humans are poorly known. The aim of the present study was to evaluate the organ-specific changes in BF during a mixed-meal and incretin infusions. Design A non-randomized intervention study of 10 healthy adults to study splanchnic BF regulation was performed. Methods Effects of glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) infusions and mixed-meal were tested in 10 healthy, glucose tolerant subjects using PET-MRI multimodal imaging technology. Intestinal and pancreatic BF and blood volume (BV) were measured with 15O-water and 15O-carbon monoxide, respectively. Results Ingestion of a mixed-meal led to an increase in pancreatic and jejunal BF, whereas duodenal BF was unchanged. Infusion of GIP and GLP-1 reduced BF in the pancreas. However, GIP infusion doubled blood flow in the jejunum with no effect of GLP-1. Conclusion Together, our data suggest that meal ingestion leads to increases in pancreatic BF accompanied by a GIP-mediated increase in jejunal but not duodenal blood flow.
Aims/hypothesis The mechanisms for improved glycemic control after bariatric surgery in subjects with type 2 diabetes (T2D) are not fully known. We hypothesized that dynamic hepatic blood responses ...to a mixed-meal are changed after bariatric surgery in parallel with an improvement in glucose tolerance. Methods A total of ten morbidly obese subjects with T2D were recruited to receive a mixed-meal and a glucose-dependent insulinotropic polypeptide (GIP) infusion before and early after (within a median of less than three months) bariatric surgery, and hepatic blood flow and volume (HBV) were measured repeatedly with combined positron emission tomography/MRI. Ten lean non-diabetic individuals served as controls. Results Bariatric surgery leads to a significant decrease in weight, accompanied with an improved β-cell function and glucagon-like peptide 1 (GLP-1) secretion, and a reduction in liver volume. Blood flow in portal vein (PV) was increased by 1.65-fold (P = 0.026) in response to a mixed-meal in subjects after surgery, while HBV decreased in all groups (P < 0.001). When the effect of GIP infusion was tested separately, no change in hepatic arterial and PV flow was observed, but HBV decreased as seen during the mixed-meal test. Conclusions/interpretation Early after bariatric surgery, PV flow response to a mixed-meal is augmented, improving digestion and nutrient absorption. GIP influences the post-prandial reduction in HBV thereby diverting blood to the extrahepatic sites.
Gastric bypass surgery (GB), and to lesser degree sleeve gastrectomy (SG), predispose to prandial hypoglycemia. Diagnosis is challenging since hypoglycemic symptoms overlap with those of dumping ...syndrome. Here, we sought to determine whether symptoms distribution after meal challenge differ among GB vs. SG or non-operated controls (CN), and between GB with and without documented hypoglycemia syndrome as per Whipple's triad. Plasma glucose and prandial symptoms were obtained every 15 min during a 3-h mixed-meal test in matched, non-diabetic groups of 11 hypoglycemic-GB (HGB), 18 asymptomatic-GB (AGB), 24 SG and 5 CN. Symptoms were stratified into autonomic (breathlessness, fatigue, sleepiness, palpitation, restlessness, dizziness, shaking, sweating, feeling warm) and neuroglycopenic (fainting or syncope, impaired cognition, irritability, seizure), and gastrointestinal (GI) symptoms. Peak-to-nadir glycemic excursion was higher in GB vs. SG vs. CN (137±8.0 vs. 86.6±6.0 vs. 48.6±9.1 mg/dl, respectively, P < 0.001). GI symptoms were experienced mainly within first 60 minutes of meal study in all 4 groups (P < 0.001 for time factor), and their average score was higher in GB compared with SG (by 2-fold) and CN subjects (by 14-fold, P < 0.01 for group factor). Likewise, autonomic symptoms were most prevalent during the early phase of the meal (P < 0.05), and their average score tended to be higher in GB compared with SG (by 2-fold) and CN subjects (by 5-fold, P = 0.06 for group factor). Neither GI nor autonomic symptom scores differed among HGB and AGB. Given the low rate of chemical hypoglycemia, neuroglycopenic symptoms were rare and not different among the groups. We conclude that the majority of autonomic symptoms, often mistaken for hypoglycemia, occur in early prandial phase and are not different among GB with and without documented hypoglycemia syndrome. Thus, presence of neuroglycopenia is critical in diagnosis of clinical hypoglycemia in this population.
Disclosure
H. Honka: None. S. Al-rifaie: None. A. Gastaldelli: Advisory Panel; Pfizer Inc., Novo Nordisk, Merck Sharp & Dohme Corp., Boehringer Ingelheim International GmbH, Consultant; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Fractyl Health, Inc., Merck Sharp & Dohme Corp., Other Relationship; Pfizer Inc., Speaker's Bureau; Eli Lilly and Company. M. Salehi: None.
Funding
National Institute of Diabetes and Digestive and Kidney Diseases (DK105379)
Gastric bypass (GB) increases postprandial glucose excursion, which in turn can predispose to the late complication of hypoglycemia. Diagnosis remains challenging and requires documentation of ...symptoms associated with low glucose and relief of symptom when glucose is normalized (Whipple triad).
To compare the yield of mixed meal test (MMT) and continuous glucose monitoring system (CGMS) in detecting hypoglycemia after GB.
The study was conducted at General Clinical Research Unit, Cincinnati Children's Hospital (Cincinnati, OH, USA).
Glucose profiles were evaluated in 15 patients with documented recurrent clinical hypoglycemia after GB, 8 matched asymptomatic GB subjects, and 9 healthy weight-matched nonoperated controls using MMT in a control setting and CGMS under free-living conditions.
Patients with prior GB had larger glucose variability during both MMT and CGMS when compared with nonsurgical controls regardless of their hypoglycemic status. Sensitivity (71 vs 47%) and specificity (100 vs 88%) of MMT in detecting hypoglycemia was superior to CGMS.
Our findings indicate that a fixed carbohydrate ingestion during MMT is a more reliable test to diagnose GB-related hypoglycemia compared with CGMS during free-living state.
The mechanisms responsible for the positive and unexpected cardiovascular effects of sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists in patients with type 2 ...diabetes remain to be defined. It is likely that some of the beneficial cardiac effects of these antidiabetic drugs are mediated, in part, by altered myocardial metabolism. Common cardiometabolic disorders, including the metabolic (insulin resistance) syndrome and type 2 diabetes, are associated with altered substrate utilization and energy transduction by the myocardium, predisposing to the development of heart disease. Thus, the failing heart is characterized by a substrate shift toward glycolysis and ketone oxidation in an attempt to meet the high energetic demand of the constantly contracting heart. This review examines the metabolic pathways and clinical implications of myocardial substrate utilization in the normal heart and in cardiometabolic disorders, and discusses mechanisms by which antidiabetic drugs and metabolic interventions improve cardiac function in the failing heart.
To determine the effect of endogenous glucagon-like peptide 1 (GLP-1) on prandial counterregulatory response to hypoglycaemia after gastric bypass (GB).
Glucose fluxes, and islet-cell and gut hormone ...responses before and after mixed-meal ingestion, were compared during a hyperinsulinaemic-hypoglycaemic (~3.2 mmol/L) clamp with and without a GLP-1 receptor (GLP-1R) antagonist exendin-(9-39) infusion in non-diabetic patients who had previously undergone GB compared to matched participants who had previously undergone sleeve gastrectomy (SG) and non-surgical controls.
Exendin-(9-39) infusion raised prandial endogenous glucose production (EGP) response to insulin-induced hypoglycaemia in the GB group but had no consistent effect on EGP response among the SG group or non-surgical controls (p < 0.05 for interaction). The rates of systemic appearance of ingested glucose or prandial glucose utilization did not differ among the three groups or between studies with and without exendin-(9-39) infusion. Blockade of GLP-1R had no effect on insulin secretion or insulin action but enhanced prandial glucagon in all three groups.
These results indicate that impaired post-meal glucose counterregulatory response to hypoglycaemia after GB is partly mediated by endogenous GLP-1, highlighting a novel pathogenic mechanism of GLP-1 in developing hypoglycaemia in this population.
Background
Altered prandial glycemic response after Roux‐en‐Y gastric bypass (RYGB) is exaggerated in patients with post‐RYGB hypoglycemia. Increased contribution of glucagon‐like peptide 1 (GLP‐1) ...to prandial insulin secretion plays a key role in developing hypoglycemia after RYGB, but the role of nonhormonal gut factors remains unknown. Here, the effect of vagal activation on prandial bile acid (BA) composition in relation to glucose, insulin and gut hormone responses was examined in a small size group of nondiabetic subjects after RYGB with intact gallbladder compared to nonoperated controls.
Methods
Concentrations of blood glucose, hormones, and BAs were measured in two RYGB subjects with documented hypoglycemia (HGB), three asymptomatic RYGB‐treated subjects (AGB), and four nonoperated controls with intact gallbladders during a meal‐tolerance test with (MTT‐Sham) and without (MTT) preceding modified sham feeding (chew and spit).
Key Results
Meal ingestion raised serum total BAs in RYGB‐treated subjects without any effect in nonoperated controls. Modified sham feeding similarly increased meal‐induced responses of conjugated BAs (CBAs) in all subjects (p < 0.05 compared to MTT alone), whereas unconjugated BAs (UBAs), mainly deoxycholic and chenodeoxycholic acid, were raised only in the HGB group (p < 0.001 for interaction). Prandial UBAs had an inverse correlation with glucose nadir (r = −0.75, p < 0.05) and were directly associated with ISR and GLP‐1 during MTT‐Sham.
Conclusions & Inferences
In this small cohort, vagal activation by modified sham feeding increases prandial CBAs in both operated and nonoperated subjects but enhances UBAs only in patients with documented post‐RYGB hypoglycemia. Our findings highlight a potential role for nonhormonal gut factors, such as BA and gut microbiome, in glucose abnormalities after RYGB.
The effects of Roux‐en‐Y gastric bypass (RYGB) surgery and vagal activation by modified sham feeding on enterohepatic circulation of bile acids after meal ingestion. CA, cholic acid; CBAs, conjugated bile acids; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; FGF19; fibroblast growth factor 19; HBG, patients with recurrent documented hypoglycemia after RYGB; TBAs, total bile acids; UDCA, ursodeoxycholic acid; UBAs, unconjugated bile acids.
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