Influence of long-term diabetes on liver glycogen metabolism in the rat

Ferrannini, Eleuterio; Lanfranchi, Alberto; Rohner‐Jeanrenaud, Françoise; Manfredini, Giulia; Werve, Gérald van de

doi:10.1016/0026-0495(90)90170-h

Cited by 49 publications

(26 citation statements)

References 27 publications

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“…We did not measure glucagon levels in our experiments, but the STZ rat model is known to display relative hyperglucagonemia. Even if glucagon levels are normal (15,62) there is no insulin to oppose its actions, leading to a permanent and poorly controlled catabolic state characterized by the stimulation of endogenous glucose production and lipid mobilization. In our study, because we used short-acting insulin in twice daily injections, STZ rats receiving treatment would remain relatively hyperglucagonemic with increasing time after the injections.…”

Section: Discussionmentioning

confidence: 99%

Restoration of direct pathway glycogen synthesis flux in the STZ-diabetes rat model by insulin administration

Soares

Carvalho

Veiga

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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-Type 1 diabetes subjects are characterized by impaired direct pathway synthesis of hepatic glycogen that is unresponsive to insulin therapy. Since it is not known whether this is an irreversible defect of insulin-dependent diabetes, direct and indirect pathway glycogen fluxes were quantified in streptozotocin (STZ)-induced diabetic rats and compared with STZ rats that received subcutaneous or intraperitoneal insulin (I-SC or I-IP). Three groups of STZ rats were studied at 18 days post-STZ treatment. One group was administered I-SC and another I-IP as two daily injections of short-acting insulin at the start of each light and dark period for days 9 -18. A third group did not receive any insulin, and a fourth group of nondiabetic rats was used as control. Glycogen synthesis via direct and indirect pathways, de novo lipogenesis, and gluconeogenesis were determined over the nocturnal feeding period using deuterated water. Direct pathway was residual in STZ rats, and glucokinase activity was also reduced significantly from control levels. Insulin administration restored both net glycogen synthesis via the direct pathway and glucokinase activity to nondiabetic control levels and improved the lipogenic pathway despite an inefficient normalization of the gluconeogenic pathway. We conclude that the reduced direct pathway flux is not an irreversible defect of insulindependent diabetes. indirect pathway; 2 H-nuclear magnetic resonance; glucokinase; de novo lipogenesis TYPE 1 DIABETES IS CHARACTERIZED by significant alterations in hepatic carbohydrate and lipid metabolism resulting from insulin insufficiency, and impairment of postprandial glycogen synthesis is among the best studied of these characteristics. Hepatic glycogen is synthesized via two pathways, the classical direct pathway from intact glucose units and the indirect pathway by which glucose is first metabolized to 3-carbon intermediates (pyruvate and further to lactate), followed by gluconeogenic resynthesis into glucose 6-phosphate (G6P) (Fig.

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Section: Discussionmentioning

confidence: 99%

Restoration of direct pathway glycogen synthesis flux in the STZ-diabetes rat model by insulin administration

Soares

Carvalho

Veiga

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…Then, beta-cytotoxic drugs, such as streptozotocin (STZ), are used in laboratory animals. In general, animals with STZ-induced diabetes present reduced hepatic capacity to synthesize glycogen during acute phase of diabetes 12 . Since the liver controls glucose homeostasis and there are no studies relating diabetes and cigarette smoke exposure.…”

Section: Introductionmentioning

confidence: 98%

Association of diabetes and cigarette smoke exposure on the glycemia and liver glycogen of pregnant Wistar rats

et al. 2008

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Purpose:To evaluate cigarette smoke exposure and/or diabetes association effects on the glycemia and liver glycogen levels of pregnant Wistar rats. Methods: 60 adult rats were randomly distributed into (n=10/group): non-diabetic exposed to filtered air (G1); non-diabetic exposed to cigarette smoke only before pregnancy (G2); non-diabetic exposed to cigarette smoke before and during pregnancy (G3); diabetic exposed to filtered air (G4); diabetic exposed to cigarette smoke only before pregnancy (G5), and diabetic exposed to cigarette smoke before and during pregnancy (G6). Glycemia was determined at days 0 and 21 of pregnancy. Liver samples were collected for liver glycogen determinations. Results: At day 21 of pregnancy, glycemia was higher in G5 and G6 compared to G4 group. G2 (2.43±0.43), G3 (3.20±0.49), G4 (2.62±0.34), G5 (2.65±0.27) and G6 groups (1.94±0.35) presented decreased liver glycogen concentrations compared to G1 (4.20±0.18 mg/100mg liver tissue) (p<0.05). G5 and G6 groups presented decreased maternal weight gain and litter weight. Conclusions: Severe diabetes and cigarette smoke exposure, alone or associated, caused impairment in liver glycogen storage at term pregnancy. Due to the fact that liver glycogen storages were considered determinant for glucose tolerance, it is relevant to point out a rigid clinical glycemic control and to stop smoking so earlier in pregnancy programming. Key words: Diabetes Mellitus, Experimental. Pregnancy. Glycogen. Tobacco Smoke Pollution. Glycemia. Rats. RESUMOObjetivo: Avaliar a associação da exposição à fumaça de cigarro e/ou diabete sobre a glicemia e concentrações de glicogênio hepático em ratas Wistar prenhes. Métodos: 60 ratas adultas foram distribuídas aleatoriamente em seis grupos (n=10/grupo): não-diabético exposto ao ar filtrado (G1); não-diabético exposto à fumaça de cigarro antes da prenhez (G2); não-diabético exposto à fumaça de cigarro antes e durante a prenhez (G3); diabético exposto ao ar filtrado (G4); diabético exposto à fumaça de cigarro antes da prenhez (G5); diabético exposto à fumaça de cigarro antes e durante a prenhez (G6). A glicemia foi determinada nos dias 0 e 21 de prenhez. Foram coletadas amostras de fígado para dosagens de glicogênio. Resultados: No 21º dia de prenhez, a glicemia foi maior nos grupos G5 e G6 comparados ao grupo G4. Os grupos G2 (2,43±0,43), G3 (3,20±0,49), G4 (2,62±0,34), G5 (2,65±0,27) e G6 (1,94±0,35) apresentaram concentrações de glicogênio diminuídas comparados ao grupo G1 (4,20±0,18 mg/100mg) (p <0.05). Os grupos G5 e G6 apresentaram ganho de peso materno e peso da ninhada diminuídos. Conclusões: O diabete grave e a exposição à fumaça de cigarro, sozinhos ou associados, causaram prejuízo no armazenamento de glicogênio na prenhez a termo. Devido ao fato dos estoques de glicogênio serem determinantes para a tolerância à glicose, é imprescindível indicar um rígido controle glicêmico e deixar de fumar antes da gestação. Descritores: Diabetes Mellitus Experimental. Gravidez. Glicogênio. Poluição por Fumaça de Tab...

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“…GS activity often becomes dysregulated in steatosis, exacerbating the already existing dysglycemia (12,17,18). Recent reports have shown that hepatic overexpression of the G-regulatory subunits of PP1 increased hepatic glycogen accumulation, protected mice from fasting hypoglycemia, and accelerated postprandial blood glucose clearance in mice fed a chow diet or an HFD or in rats with streptozotocininduced diabetes (15,19,20).…”

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confidence: 99%

“…In diabetes and obesity, metabolism of glycogen in the liver is affected when triglyceride accumulation reaches levels that manifest pathologically as fatty liver (12,16). GS activity often becomes dysregulated in steatosis, exacerbating the already existing dysglycemia (12,17,18).…”

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confidence: 99%

“…With CD36 emerging as a key player or even perceived as a causative factor in fatty liver and the associated metabolic syndrome, we hypothesize that CD36 may play an important role in energy metabolism in the liver, including the homeostasis of glycogen, which is known to be disrupted in diabetes and to contribute to the manifestation of dysglycemia (11)(12)(13). Glycogen is formed in the liver primarily in the postprandial high blood glucose state.…”

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confidence: 99%

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Hepatic Overexpression of CD36 Improves Glycogen Homeostasis and Attenuates High-Fat Diet-Induced Hepatic Steatosis and Insulin Resistance

Garbacz

Miller

et al. 2016

Molecular and Cellular Biology

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The common complications in obesity and type 2 diabetes include hepatic steatosis and disruption of glucose-glycogen homeostasis, leading to hyperglycemia. Fatty acid translocase (FAT/CD36), whose expression is inducible in obesity, is known for its function in fatty acid uptake. Previous work by us and others suggested that CD36 plays an important role in hepatic lipid homeostasis, but the results have been conflicting and the mechanisms were not well understood. In this study, by using CD36-overexpressing transgenic (CD36Tg) mice, we uncovered a surprising function of CD36 in regulating glycogen homeostasis. Overexpression of CD36 promoted glycogen synthesis, and as a result, CD36Tg mice were protected from fasting hypoglycemia. When challenged with a high-fat diet (HFD), CD36Tg mice showed unexpected attenuation of hepatic steatosis, increased very low-density lipoprotein (VLDL) secretion, and improved glucose tolerance and insulin sensitivity. The HFD-fed CD36Tg mice also showed decreased levels of proinflammatory hepatic prostaglandins and 20-hydroxyeicosatetraenoic acid (20-HETE), a potent vasoconstrictive and proinflammatory arachidonic acid metabolite. We propose that CD36 functions as a protective metabolic sensor in the liver under lipid overload and metabolic stress. CD36 may be explored as a valuable therapeutic target for the management of metabolic syndrome. Individuals with metabolic syndrome or type 2 diabetes are susceptible to nonalcoholic fatty liver disease (1) and disruption of hepatic glucose and glycogen homeostasis (2). Hepatic steatosis is defined as an excess accumulation of fat in hepatocytes. Previous reports suggested that fatty acid translocase (FAT/CD36) plays an important role in hepatic lipid homeostasis (3-6). CD36 is a multiligand class B scavenger receptor with high affinity for lipids and lipid-containing ligands. CD36 is known for its lipid uptake function in macrophages, skeletal muscle, and the heart. However, the role of CD36 in hepatic lipid metabolism is still not well understood, and the available evidence is often conflicting, partly due to the lack of a reliable in vivo liver-specific gain-of-function model to specifically evaluate the function of CD36 in the liver.The basal expression of CD36 in the liver is low; however, it is highly inducible by a high-fat diet (HFD) (3). The hepatic expression of CD36 is under the transcriptional control of the nuclear receptors: liver X receptor (LXR), pregnane X receptor (PXR), peroxisome proliferator-activated receptors (PPARs), and the aryl hydrocarbon receptor (AhR) (4). Some studies have suggested that hepatic CD36, by functioning as a fatty acid transporter, has a role in the pathogenesis of hepatic steatosis (3), obesity (7, 8), and age-related hepatic steatosis (5). Furthermore, we and others reported that induction of CD36 was a common factor in fatty liver following the activation of LXR and PXR (6, 9). On the other hand, recent reports suggested that CD36 signaling might actually be beneficial in preventing fatty live...

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Influence of long-term diabetes on liver glycogen metabolism in the rat

Cited by 49 publications

References 27 publications

Restoration of direct pathway glycogen synthesis flux in the STZ-diabetes rat model by insulin administration

Restoration of direct pathway glycogen synthesis flux in the STZ-diabetes rat model by insulin administration

Association of diabetes and cigarette smoke exposure on the glycemia and liver glycogen of pregnant Wistar rats

Hepatic Overexpression of CD36 Improves Glycogen Homeostasis and Attenuates High-Fat Diet-Induced Hepatic Steatosis and Insulin Resistance

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