Role of Excess Glycogenolysis in Fasting Hyperglycemia Among Pre-Diabetic and Diabetic Zucker (<i>fa/fa</i>) Rats

Jin, Eunsook S.; Park, Byung Hyun; Sherry, A. Dean; Malloy, Craig R.

doi:10.2337/db06-0717

Cited by 15 publications

(27 citation statements)

References 35 publications

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“…These data suggest that the hepatic TCA cycle is significantly more active in obese postprandial cats, but pyruvate cycling appears to modulate gluconeogenesis and EGP. A regulatory role for pyruvate cycling has also been described in Zucker (fa/fa) rats (34). We have previously shown that fasted female obese cats had similar changes, including higher pyruvate cycling (41).…”

Section: Discussionmentioning

confidence: 91%

Effect of macronutrients, age, and obesity on 6- and 24-h postprandial glucose metabolism in cats

Hoenig

Jordan

Glushka

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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. Effect of macronutrients, age, and obesity on 6-and 24-h postprandial glucose metabolism in cats. Am J Physiol Regul Integr Comp Physiol 301: R1798 -R1807, 2011. First published September 21, 2011 doi:10.1152/ajpregu.00342.2011.-Obesity and age are risk factors for feline diabetes. This study aimed to test the hypothesis that age, long-term obesity, and dietary composition would lead to peripheral and hepatorenal insulin resistance, indicated by higher endogenous glucose production (EGP) in the fasted and postprandial state, higher blood glucose and insulin, and higher leptin, free thyroxine, and lower adiponectin concentrations. Using triple tracer-2 H2O, [U-13 C3] propionate, and [3,4-13 C2] glucose infusion, and indirect calorimetry-we investigated carbohydrate and fat metabolic pathways in overnight-fasted neutered cats (13 young lean, 12 old lean, and 12 old obese), each fed three different diets (high protein with and without polyunsaturated fatty acids, and high carbohydrate) in a crossover design. EGP was lowest in fasted and postprandial obese cats despite peripheral insulin resistance, indicated by hyperinsulinemia. Gluconeogenesis was the most important pathway for EGP in all groups, but glycogen contributed significantly. Insulin and leptin concentrations were higher in old than in young lean cats; adiponectin was lowest in obese cats but surprisingly highest in lean old cats. Diet had little effect on metabolic parameters. We conclude that hepatorenal insulin resistance does not develop in the fasted or postprandial state, even in long-term obese cats, allowing the maintenance of euglycemia through lowering EGP. Glycogen plays a major role in EGP, especially in lean fasted cats, and in the postprandial state. Aging may predispose to insulin resistance, which is a risk factor for diabetes in cats. Mechanisms underlying the high adiponectin of healthy old lean cats need to be further explored. nuclear magnetic resonance spectroscopy; adipocytokines; indirect calorimetry; glycogenolysis; insulin resistance; endogenous glucose production IN MAN AND IN CATS, obesity and age are factors in the development of diabetes (8, 69). As in people, the incidence of feline obesity and diabetes has increased dramatically in the past 3 decades (2,8). Obesity is now the most common nutritional disorder in cats, and diabetes is one of the most common endocrinopathies in aging cats. Little is known about the metabolic changes in obese cats and the influence of age and food intake on metabolic parameters that contribute to increasing obesity and diabetes.Cats are obligatory carnivores that naturally subsist on a high-protein and high-fat diet. It has been stated anecdotally that glycogen contributes less to glucose production in cats than other species. Rogers et al. (61) reported that cats cannot readily adapt their sources of glucose production, a notion that has been refuted by others (25,26,65,66). We have previously shown that, in fasted cats, fractional gluconeogenesis (GNG) and glycogenolysis is similar to hum...

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Section: Discussionmentioning

confidence: 91%

Effect of macronutrients, age, and obesity on 6- and 24-h postprandial glucose metabolism in cats

Hoenig

Jordan

Glushka

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Very low rates of glycogenolysis have been reported in one rat strain fasting for 24 h, but in obese rats (fa/fa) hepatic glycogen was maintained and contributed 10 -15% of EGP (35). We did not measure hepatic glycogen concentration, but it seems that glycogen stores were depleted early in fasting.…”

Section: Discussionmentioning

confidence: 99%

Gluconeogenesis is associated with high rates of tricarboxylic acid and pyruvate cycling in fasting northern elephant seals

Champagne

Houser

Fowler

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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Champagne CD, Houser DS, Fowler MA, Costa DP, Crocker DE. Gluconeogenesis is associated with high rates of tricarboxylic acid and pyruvate cycling in fasting northern elephant seals. Am J Physiol Regul Integr Comp Physiol 303: R340 -R352, 2012. First published June 6, 2012 doi:10.1152/ajpregu.00042.2012.-Animals that endure prolonged periods of food deprivation preserve vital organ function by sparing protein from catabolism. Much of this protein sparing is achieved by reducing metabolic rate and suppressing gluconeogenesis while fasting. Northern elephant seals (Mirounga angustirostris) endure prolonged fasts of up to 3 mo at multiple life stages. During these fasts, elephant seals maintain high levels of activity and energy expenditure associated with breeding, reproduction, lactation, and development while maintaining rates of glucose production typical of a postabsorptive mammal. Therefore, we investigated how fasting elephant seals meet the requirements of glucosedependent tissues while suppressing protein catabolism by measuring the contribution of glycogenolysis, glycerol, and phosphoenolpyruvate (PEP) to endogenous glucose production (EGP) during their natural 2-mo postweaning fast. Additionally, pathway flux rates associated with the tricarboxylic acid (TCA) cycle were measured specifically, flux through phosphoenolpyruvate carboxykinase (PEPCK) and pyruvate cycling. The rate of glucose production decreased during the fast (F 1,13 ϭ 5.7, P ϭ 0.04) but remained similar to that of postabsorptive mammals. The fractional contributions of glycogen, glycerol, and PEP did not change with fasting; PEP was the primary gluconeogenic precursor and accounted for ϳ95% of EGP. This large contribution of PEP to glucose production occurred without substantial protein loss. Fluxes through the TCA cycle, PEPCK, and pyruvate cycling were higher than reported in other species and were the most energetically costly component of hepatic carbohydrate metabolism. The active pyruvate recycling fluxes detected in elephant seals may serve to rectify gluconeogeneic PEP production during restricted anaplerotic inflow in these fasting-adapted animals. pinnipedia; nuclear magnetic resononace; glucose production NEARLY ALL ANIMALS experience periods of food deprivation, frequently as a result of seasonal variation in food availability or the requirements of reproduction. Animals usually respond to fasting by reducing their overall metabolic rate, increasing their reliance on lipid reserves to meet energetic costs, and conserving lean tissue to preserve vital organ function (11). Select tissues, however, cannot use lipid as an energy source, and some protein must be degraded to supply the precursors for gluconeogenesis to meet the energy needs of these tissuesincluding the brain, red blood cells, and renal medulla. The commitment of amino acids to gluconeogenic pathways depletes protein reserves, compromising vital organ function in fasting animals (24). Terminal starvation occurs once lipid reserves are depleted or the loss of prote...

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“…If skeletal muscle resembles heart, where this discrepancy is broadly independent of ATP turnover (32) (in effect, a constant error), the 20 -40% P i /ATP exchange defect in HF (21a) and other IR states (4,28,29,36) presumably underestimates that in ATP synthesis. However, the similar percent defects in P i /ATP exchange and tricarboxylic cycle (TCAC) flux measured by 13 C MRS in IR (4,28,29) suggest that the discrepancy is turnover dependent (a proportional error). This is not resolved by the observations that triiodothyronine (14,22) and 2,4-dinitrophenol (14) decrease, whereas uncoupling protein-3 knockout increases (8), the ratio of P i /ATP exchange to TCAC flux [a qualitative index of coupling (15,16)] or that 2,4-dinitrophenol does not affect directly measured glycolytic exchange (14).…”

Section: Absolute Ratesmentioning

confidence: 99%

“…Assumptions: P:O ϭ 2.16 from mouse ischemic 31 P MRS/NIRS (shown as linked points) (24,25); human leg muscle mass ϭ 10 kg; V O2/TCAC flux ϭ 3, and 1 mol O2 ϭ 25.5 l (10); wet/dry ϭ 4.35, and cell water ϭ 0.67 l/kg (7). Dashed lines give overall means of published values, for which rat/human ratio is ϳ3:5 by V O2 and 13 C MRS (cf expected ϳ4) and mouse/human ratio is ϳ4:7 by ischemic 31 P MRS/NIRS and 13 C MRS (cf expected ϳ7); Pi/ATP exchange is similar in human and rat (21a) but lower in the single mouse study (8). B: rates in rat muscle vs. PCr concentration ([PCr]) relative to resting values.…”

Section: Flux Vs Capacity Supply Vs Demandmentioning

confidence: 99%

“…A: resting rates in healthy human, rat, and mouse muscle. Each point is 1 published mean: 1 ϭ 31 P magnetic resonance saturation (MRS) transfer (ST) Pi/ATP exchange in human (6,22,28,29,36), rat (7, 14 -16, 21a), and mouse (8) [Laurent et al (21a) reported the highest rat value]; 2 ϭ 13 C MRS tricarboxylic cycle (TCAC) rate in human (4,22,28), rat (13)(14)(15)(16), and mouse (8); 3 ϭ arteriovenous-difference (AVD) V O2 in human (3,10,39) (11,17,27). Assumptions: P:O ϭ 2.16 from mouse ischemic 31 P MRS/NIRS (shown as linked points) (24,25); human leg muscle mass ϭ 10 kg; V O2/TCAC flux ϭ 3, and 1 mol O2 ϭ 25.5 l (10); wet/dry ϭ 4.35, and cell water ϭ 0.67 l/kg (7).…”

Section: Flux Vs Capacity Supply Vs Demandmentioning

confidence: 99%

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The interpretation of abnormal ³¹P magnetic resonance saturation transfer measurements of P_i/ATP exchange in insulin-resistant skeletal muscle

Kemp¹

2008

American Journal of Physiology-Endocrinology and Metabolism

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TO THE EDITOR: To study relationships between muscle mitochondrial function, fatty acid oxidation, intramyocellular lipid (IMCL), and insulin resistance (IR), Laurent et al. (21a) measured P i /ATP exchange by 31 P magnetic resonance saturation (MRS) transfer (ST) in resting rat muscle and found that it decreased transiently by high dietary fat (HF) intake. Following precedent, they identified P i /ATP exchange with mitochondrial ATP synthesis, noting that "actual rates obtained . . . in rats at rest are in excellent agreement with recent human data," and took the decrease as evidence of mitochondrial dysfunction (21a). I would like to make two points about absolute rates and pathophysiological logic. Absolute RatesGiven the allometry of basal metabolic rate (34), to which it makes a large contribution (33), resting muscle ATP turnover should presumably scale with weight (Ϫ0.25) , making it approximately four times greater in rat (ϳ7 in mouse) than in human. Unlike P i /ATP exchange (21a), published measurements by several other methods seem roughly consistent with this (Fig. 1A). Moreover, although "there is no gold standard against which the ATP synthesis rate measured by 31 P saturation transfer can easily be validated" (21a), the estimates it gives are notably high (Fig. 1A). For P i /ATP exchange to validly measure mitochondrial ATP synthesis (i.e., net flux through F 1 F 0 -ATPase) requires this to be far from equilibrium [as measurements in vitro support, at least at high turnover (21)] and glycolytic P i /ATP exchange (catalyzed by glyceraldehyde-3-phosphate dehydrogenase and 3-phosphoglycerate kinase) to be small (7, 15, 21a, 32). No direct comparisons have been made, but suprabasal P i /ATP exchange rates in stimulated rat muscle were noted (7) to be approximately consistent with O 2 consumption (12) and phosphocreatine (PCr) kinetic (35) data and with poststimulation PCr resynthesis rates (38). However, upon reexamination (Fig. 1B) these comparisons do not rule out appreciable glycolytic P i /ATP exchange. If skeletal muscle resembles heart, where this discrepancy is broadly independent of ATP turnover (32) (in effect, a constant error), the 20 -40% P i /ATP exchange defect in HF (21a) and other IR states (4,28,29,36) presumably underestimates that in ATP synthesis. However, the similar percent defects in P i /ATP exchange and tricarboxylic cycle (TCAC) flux measured by 13 C MRS in IR (4,28,29) suggest that the discrepancy is turnover dependent (a proportional error). This is not resolved by the observations that triiodothyronine (14, 22) and 2,4-dinitrophenol (14) decrease, whereas uncoupling protein-3 knockout increases (8), the ratio of P i /ATP exchange to TCAC flux [a qualitative index of coupling (15, 16)] or that 2,4-dinitrophenol does not affect directly measured glycolytic exchange (14). Flux Vs. Capacity, Supply Vs. DemandThe distinction between flux and capacity is why "maximal enzyme activities do not necessarily reflect actual flux through metabolic pathways" (21a, 29). On the conventio...

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Role of Excess Glycogenolysis in Fasting Hyperglycemia Among Pre-Diabetic and Diabetic Zucker (fa/fa) Rats

Cited by 15 publications

References 35 publications

Effect of macronutrients, age, and obesity on 6- and 24-h postprandial glucose metabolism in cats

Effect of macronutrients, age, and obesity on 6- and 24-h postprandial glucose metabolism in cats

Gluconeogenesis is associated with high rates of tricarboxylic acid and pyruvate cycling in fasting northern elephant seals

The interpretation of abnormal ³¹P magnetic resonance saturation transfer measurements of P_i/ATP exchange in insulin-resistant skeletal muscle

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Role of Excess Glycogenolysis in Fasting Hyperglycemia Among Pre-Diabetic and Diabetic Zucker (fa/fa) Rats

Cited by 15 publications

References 35 publications

Effect of macronutrients, age, and obesity on 6- and 24-h postprandial glucose metabolism in cats

Effect of macronutrients, age, and obesity on 6- and 24-h postprandial glucose metabolism in cats

Gluconeogenesis is associated with high rates of tricarboxylic acid and pyruvate cycling in fasting northern elephant seals

The interpretation of abnormal 31P magnetic resonance saturation transfer measurements of Pi/ATP exchange in insulin-resistant skeletal muscle

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The interpretation of abnormal ³¹P magnetic resonance saturation transfer measurements of P_i/ATP exchange in insulin-resistant skeletal muscle