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Glucagon-Like Peptide 1 (GLP-1) has insulin-like effects on myocardial glucose uptake which may contribute to its beneficial effects in the setting of myocardial ischemia. Whether these effects are different in the setting of obesity or type 2 diabetes (T2DM) requires investigation. We examined the cardiometabolic actions of GLP-1 (7–36) in lean and obese/T2DM humans, and in lean and obese Ossabaw swine. GLP-1 significantly augmented myocardial glucose uptake under resting conditions in lean humans, but this effect was impaired in T2DM. This observation was confirmed and extended in swine, where GLP-1 effects to augment myocardial glucose uptake during exercise were seen in lean but not in obese swine. GLP-1 did not increase myocardial oxygen consumption or blood flow in humans or in swine. Impaired myocardial responsiveness to GLP-1 in obesity was not associated with any apparent alterations in myocardial or coronary GLP1-R expression. No evidence for GLP-1 mediated activation of cAMP/PKA or AMPK signaling in lean or obese hearts was observed. GLP-1 treatment augmented p38-MAPK activity in lean, but not obese cardiac tissue. Taken together, these data provide novel evidence indicating that the cardiometabolic effects of GLP-1 are attenuated in obesity and T2DM, via mechanisms that may involve impaired p38-MAPK signaling.

-Altered myocardial fuel selection likely underlies cardiac disease risk in diabetes, affecting oxygen demand and myocardial metabolic flexibility. We investigated myocardial fuel selection and metabolic flexibility in human type 2 diabetes mellitus (T2DM), using positron emission tomography to measure rates of myocardial fatty acid oxidation {16-[ 18 F]fluoro-4-thia-palmitate (FTP)} and myocardial perfusion and total oxidation ([ 11 C]acetate). Participants underwent paired studies under fasting conditions, comparing 3-h insulin ϩ glucose euglycemic clamp conditions (120 mU·m Ϫ2 ·min Ϫ1 ) to 3-h saline infusion. Lean controls (n ϭ 10) were compared with glycemically controlled volunteers with T2DM (n ϭ 8). Insulin augmented heart rate, blood pressure, and stroke index in both groups (all P Ͻ 0.01) and significantly increased myocardial oxygen consumption (P ϭ 0.04) and perfusion (P ϭ 0.01) in both groups. Insulin suppressed available nonesterified fatty acids (P Ͻ 0.0001), but fatty acid concentrations were higher in T2DM under both conditions (P Ͻ 0.001). Insulin-induced suppression of fatty acid oxidation was seen in both groups (P Ͻ 0.0001). However, fatty acid oxidation rates were higher under both conditions in T2DM (P ϭ 0.003). Myocardial work efficiency was lower in T2DM (P ϭ 0.006) and decreased in both groups with the insulin-induced increase in work and shift in fuel utilization (P ϭ 0.01). Augmented fatty acid oxidation is present under baseline and insulin-treated conditions in T2DM, with impaired insulin-induced shifts away from fatty acid oxidation. This is accompanied by reduced work efficiency, possibly due to greater oxygen consumption with fatty acid metabolism. These observations suggest that improved fatty acid suppression, or reductions in myocardial fatty acid uptake and retention, could be therapeutic targets to improve myocardial ischemia tolerance in T2DM. myocardial; heart; diabetes; metabolism; metabolic flexibility; positron emission tomography ALTERATIONS IN METABOLIC SUBSTRATE uptake and metabolism are part of the phenotype that defines type 2 diabetes mellitus (T2DM) (3,4,33,39,74). The phenomenon of "metabolic flexibility" is the capacity of an organism, a tissue bed, or a cell system to switch readily among fuel types. Impaired metabolic flexibility is another phenotypic feature of T2DM (33, 66).Impaired metabolic flexibility has been demonstrated in skeletal muscle in human diabetes (32,66). This whole body effect likely arises due to effects of impaired insulin-stimulated glucose uptake, together with abnormalities in availability, uptake, and metabolism of fatty acid fuels (33,66,75).The myocardium is also affected by T2DM. The fuel needs of the heart are dramatically different than those of skeletal muscle, supporting continuous work even under resting conditions. Abnormalities in myocardial fuel selection in animal models of diabetes have been described (42,54,75), including impairments in insulin-stimulated glucose uptake and impaired suppression of myocardial fatty acid u...

OBJECTIVETo compare insulin sensitivity (M/I) and b-cell responses in youth versus adults with impaired glucose tolerance (IGT) or drug-naïve, recently diagnosed type 2 diabetes. RESEARCH DESIGN AND METHODSIn 66 youth (80.3% with IGT) and 355 adults (70.7% IGT), hyperglycemic clamps were used to measure 1) M/I, 2) acute (0-10 min [first phase]) C-peptide (ACPR g ) and insulin (AIR g ) responses to glucose, 3) steady-state C-peptide and insulin concentrations at plasma glucose of 11.1 mmol/L, and 4) arginine-stimulated maximum C-peptide (ACPR max ) and insulin (AIR max ) responses at plasma glucose >25 mmol/L. The fasting C-peptide-to-insulin ratio was used as an estimate of insulin clearance. RESULTSInsulin sensitivity was 46% lower in youth compared with adults (P < 0.001), and youth had greater acute and steady-state C-peptide (2.3-and 1.3-fold, respectively; each P < 0.001) and insulin responses to glucose (AIR g 3.0-fold and steady state 2.2-fold; each P < 0.001). Arginine-stimulated C-peptide and insulin responses were also greater in youth (1.6-and 1.7-fold, respectively; each P < 0.001). After adjustment for insulin sensitivity, all b-cell responses remained significantly greater in youth. Insulin clearance was reduced in youth (P < 0.001). Participants with diabetes had greater insulin sensitivity (P = 0.026), with lesser C-peptide and insulin responses than those with IGT (all P < 0.001) but similar insulin clearance (P = 0.109). CONCLUSIONSIn people with IGT or recently diagnosed diabetes, youth have lower insulin sensitivity, hyperresponsive b-cells, and reduced insulin clearance compared with adults. Whether these age-related differences contribute to declining b-cell function and/or impact responses to glucose-lowering interventions remains to be determined.

The Restoring Insulin Secretion (RISE) Adult Medication Study compared pharmacological approaches targeted to improve b-cell function in individuals with impaired glucose tolerance (IGT) or treatment-naive type 2 diabetes of <12 months duration. RESEARCH DESIGN AND METHODS A total of 267 adults with IGT (n = 197, 74%) or recently diagnosed type 2 diabetes (n = 70, 26%) were studied. Participants were randomized to receive 12 months of metformin alone, 3 months of insulin glargine with a target fasting glucose <5 mmol/L followed by 9 months of metformin, 12 months of liraglutide combined with metformin, or 12 months of placebo. b-Cell function was assessed using hyperglycemic clamps at baseline, 12 months (on treatment), and 15 months (3 months off treatment). The primary outcome was b-cell function at 15 months compared with baseline. RESULTS All three active treatments produced on-treatment reductions in weight and improvements in HbA 1c compared with placebo; the greatest reductions were seen in the liraglutide plus metformin group. At 12 months, glucose-stimulated C-peptide responses improved in the three active treatment groups and were greatest in the liraglutide plus metformin group, but the arginine-stimulated incremental C-peptide response was reduced in the liraglutide plus metformin group. Despite on-treatment benefits, 3 months after treatment withdrawal there were no sustained improvements in b-cell function in any treatment group. CONCLUSIONS In adults with IGT or recently diagnosed type 2 diabetes, interventions that improved b-cell function during active treatment failed to produce persistent benefits after treatment withdrawal. These observations suggest that continued intervention may be required to alter the progressive b-cell dysfunction in IGT or early type 2 diabetes.