Low carbohydrate diet decreases myocardial insulin signaling and increases susceptibility to myocardial ischemia

Abstract

Aims-Low Carbohydrate Diets (LCD) are a popular intervention for weight loss, but the effect of such diets on myocardial ischemia is not known. Myocardial energy substrates and insulin signaling pathways may be affected by these diets, and both may play a role in protection of ischemic myocardium. We investigated whether LCD increases susceptibility to cardiac injury during ischemia and reperfusion in the isolated rat heart.Main Methods-Rats were fed LCD (60% kcal from fat / 30% protein / 10% carbohydrate) or a control diet (CONT; 16% / 19% / 65%) for 2 weeks. Hearts from rats fed with LCD or CONT were isolated and subjected to normal perfusion in Langendorff mode, with 30 min global low flow ischemia (LFI; 0.3 ml/min) followed by 60 min reperfusion, or 60 min LFI followed by 120 min reperfusion.Key Findings-LCD diet led to an increase in 3-hydroxybutyrate and lower circulating insulin. LCD diet also resulted in impaired left ventricular performance during LFI, reduced recovery of function following LFI and reperfusion, and 10-to 20-fold increased injury as measured by lactate dehydrogenase release and histologic infarct area. LCD diet also led to lower myocardial glycogen stores and glycogen utilization during LFI, and lower insulin signaling as assessed by Akt phosphorylation at the end of LFI and reperfusion, but no differences in ERK 1/2 phosphorylation.Significance-These results demonstrate that LCD affects myocardial energy substrates, affects insulin signaling, and increases myocardial injury following ischemia-reperfusion in the isolated heart.

Urocortin-2 suppression of p38-MAPK signaling as an additional mechanism for ischemic cardioprotection

“…Tissues were lysed [22] and protein lysate was measured (Bio-Rad Laboratories Pte Ltd, Singapore) and normalized with 6-fold loading buffer. Samples of 25 lg protein were electrophoresed through 5-14 % SDS-PAGE gels and proteins were transferred to PVDF membranes over-night at 30 V. Western analysis used antibodies recognizing p-ERK1/2 (Thr202/Try204), total ERK1/2, p-JNK (Thr183/Tyr185), total JNK, p-P38 (Thr180/Tyr182), total p38, p-Bim (Ser69), total Bim, total Bcl-2, total Bax, p-mTOR (Ser2448), total mTOR, TNF-a, ICAM-1, and succinate dehydrogenase complex subunit A (SDHA) (Cell Signaling Technology, Research Biolabs PTE Ltd., Singapore).…”

High-fat, low-carbohydrate diet promotes arrhythmic death and increases myocardial ischemia-reperfusion injury in rats

“…Twelve-week-old, 300-g male Sprague-Dawley rats (Taconic Farms, Hudson, NY) were fed one of two diets designed similar to ones used by humans for weight loss: HFLCD (60% calories from fat, 30% from protein, 10% from carbohydrate; 5TSY; TestDiet, Richmond, IN) or a low-fat control diet (CONT; 16% fat, 19% protein, 65% carbohydrate; TestDiet 5TJM) for 2 wk. HFLCD had higher energy density than CONT (5.0 vs. 3.9 kcal/g); the source of macronutrients in the diets was listed previously (34,61). Among the total amount of fat present in each diet, both diets were designed to contain 40% saturated fatty acids (as a percentage of total fat), 40% monounsaturated fatty acids, and 20% polyunsaturated fatty acids (Table 1); the makeup is designed to be similar to the induction phase of the Atkins diet for humans (20), with macronutrient content high in protein, low in carbohydrate, and 4.8-fold higher in fat than the CONT diet.…”

Impact of high-fat, low-carbohydrate diet on myocardial substrate oxidation, insulin sensitivity, and cardiac function after ischemia-reperfusion

“…Since the 3-HB concentration and the acetoacetate concentrations are equivalent, we chose to formulate the perfused ketone concentration as twice the measured 3-HB concentration to simulate physiologic conditions and simplify carbon-13 labeling (see below). In our prior work, we found differences only in circulating ketone body and insulin concentrations in serum from animals fed the HFLCD and CONT diets, with no differences in glucose or FFA (45). To enable a comprehensive analysis of the effect of both insulin and ketone in the buffer, including an examination of possible interactions between these two factors, a total of four different buffer compositions were used, independently varying the insulin and ketone composition.…”

“…We labeled these four combinations as HI-HK, HI-LK, LI-LK, and LI-HK. These four perfusion buffers were supplied to hearts from rats fed HFLCD and CONT diet during the perfusion protocols with normal coronary flow and low-flow ischemia (LFI) (0.3 ml/min) for 60 min followed by 60 min of reperfusion, with details as described previously (45). Heart rate (HR), systolic pressure (SP), left ventricular end diastolic pressure (LVEDP), and peak positive and negative rates of change of pressure (ϩdP/dt and ϪdP/dt) were used as indices of ventricular function (DASYLab, Measurement Computing, Norton, MA).…”

“…However, the mechanisms causing these impaired responses are not fully known. HFLCD resulted in a number of alterations in circulating factors and myocardial properties that may explain poorer outcomes, including lower serum insulin and myocardial glycogen, higher serum ketone, and higher myocardial mitochondrial oxidative stress (24,45). Therefore, whether the changes of serum insulin and ketone induced by HFLCD play a role, and the combined effects of intrinsic (diet itself) and extrinsic (buffer composition) factors on cardiac function and cardiac energy substrate metabolic responses that underlie ischemia-reperfusion (I/R) injury, need further study.…”