scholarly journals Glucose Intolerance and Lipid Metabolic Adaptations in Response to Intrauterine and Postnatal Calorie Restriction in Male Adult Rats

Endocrinology ◽  
2013 ◽  
Vol 154 (1) ◽  
pp. 102-113 ◽  
Author(s):  
Meena Garg ◽  
Manikkavasagar Thamotharan ◽  
Yun Dai ◽  
Venu Lagishetty ◽  
Aleksey V. Matveyenko ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Caloric Restriction ◽  
Hepatic Glucose Production ◽  
Cell Mass ◽  
Glucose Production ◽  
Fatty Acid Transport ◽  
Β Cell ◽  
Hepatic Glucose ◽  
Glucose Clearance

Enhanced de novo lipogenesis (DNL), an adult hepatic adaption, is seen with high carbohydrate or low-fat diets. We hypothesized that ad libitum intake after prenatal calorie restriction will result in adult-onset glucose intolerance and enhanced DNL with modified lipid metabolic gene expression profile. Stable isotopes were used in 15-month-old adult male rat offspring exposed to prenatal (IUGR), pre- and postnatal (IPGR), or postnatal (PNGR) caloric restriction vs. controls (CON). IUGR vs. CON were heavier with hepatomegaly but unchanged visceral white adipose tissue (WAT), glucose intolerant with reduced glucose-stimulated insulin secretion (GSIS), pancreatic β-cell mass, and total glucose clearance rate but unsuppressed hepatic glucose production. Liver glucose transporter (Glut) 1 and DNL increased with decreased hepatic acetyl-CoA carboxylase (ACC) and fatty acid synthase but increased WAT fatty acid transport protein-1 and peroxisomal proliferator-activated receptor-γ, resistin, and visfatin gene expression. In contrast, PNGR and IPGR were lighter, had reduced visceral WAT, and were glucose tolerant with unchanged hepatic glucose production but with increased GSIS, β-cell mass, glucose clearance rate, and WAT insulin receptor. Hepatic Glut1 and DNL were also increased in lean IPGR and PNGR with increased hepatic ACC, phosphorylated ACC, and pAMPK and reduced WAT fatty acid transport protein-1, peroxisomal proliferator-activated receptor-γ, and ACCα. We conclude the following: 1) the heavy, glucose-intolerant and insulin-resistant IUGR adult phenotype is ameliorated by postnatal caloric restriction; 2) increased DNL paralleling hepatic Glut1 is a biomarker of exposure to early caloric restriction rather than the adult metabolic status; 3) hepatic lipid enzyme expression reflects GSIS rather than DNL; and 4) WAT gene expression reflects an obesogenic vs. lean phenotype.

scholarly journals Prevention of Diabetes in db/db Mice by Dietary Soy Is Independent of Isoflavone Levels

Endocrinology ◽  
2012 ◽  
Vol 153 (11) ◽  
pp. 5200-5211 ◽  
Author(s):  
Céline Zimmermann ◽  
Christopher R. Cederroth ◽  
Lucie Bourgoin ◽  
Michelangelo Foti ◽  
Serge Nef
Keyword(s):  
Glucose Homeostasis ◽  
Cell Function ◽  
Hepatic Glucose Production ◽  
Cell Mass ◽  
Glucose Production ◽  
Metabolic Effects ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Glucose Levels ◽  
Hepatic Glucose

Abstract Recent evidence points towards the beneficial use of soy proteins and isoflavones to improve glucose control and slow the progression of type 2 diabetes. Here, we used diabetic db/db mice fed a high soy-containing diet (SD) or a casein soy-free diet to investigate the metabolic effects of soy and isoflavones consumption on glucose homeostasis, hepatic glucose production, and pancreatic islet function. Male db/db mice fed with a SD exhibited a robust reduction in hyperglycemia (50%), correlating with a reduction in hepatic glucose production and preserved pancreatic β-cell function. The rapid decrease in fasting glucose levels resulted from an inhibition of gluconeogenesis and an increase in glycolysis in the liver of db/db mice. Soy consumption also prevented the loss of pancreatic β-cell mass and thus improved glucose-stimulated insulin secretion (3-fold), which partly accounted for the overall improvements in glucose homeostasis. Comparison of SD effects on hyperglycemia with differing levels of isoflavones or with purified isoflavones indicate that the beneficial physiological effects of soy are not related to differences in their isoflavone content. Overall, these findings suggest that consumption of soy is beneficial for improving glucose homeostasis and delaying the progression of diabetes in the db/db mice but act independently of isoflavone concentration.

scholarly journals Caffeamide 36-13 Regulates the Antidiabetic and Hypolipidemic Signs of High-Fat-Fed Mice on Glucose Transporter 4, AMPK Phosphorylation, and Regulated Hepatic Glucose Production

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Yueh-Hsiung Kuo ◽  
Cheng-Hsiu Lin ◽  
Chun-Ching Shih
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Glucose Transporter ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hypolipidemic Effect ◽  
Glucose Transporter 4 ◽  
High Fat ◽  
Amide Derivatives ◽  
Hepatic Glucose

This study was to investigate the antidiabetic and antihyperlipidemic effects of (E)-3-[3, 4-dihydroxyphenyl-1-(piperidin-1-yl)prop-2-en-1-one] (36-13) (TS), one of caffeic acid amide derivatives, on high-fat (HF-) fed mice. The C57BL/6J mice were randomly divided into the control (CON) group and the experimental group, which was firstly fed a HF diet for 8 weeks. Then, the HF group was subdivided into four groups and was given TS orally (including two doses) or rosiglitazone (Rosi) or vehicle for 4 weeks. Blood, skeletal muscle, and tissues were examined by measuring glycaemia and dyslipidemia-associated events. TS effectively prevented HF diet-induced increases in the levels of blood glucose, triglyceride, insulin, leptin, and free fatty acid (FFA) and weights of visceral fa; moreover, adipocytes in the visceral depots showed a reduction in size. TS treatment significantly increased the protein contents of glucose transporter 4 (GLUT4) in skeletal muscle; TS also significantly enhanced Akt phosphorylation in liver, whereas it reduced the expressions of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). Moreover, TS enhanced phosphorylation of AMP-activated protein kinase (phospho-AMPK) both in skeletal muscle and liver tissue. Therefore, it is possible that the activation of AMPK by TS resulted in enhanced glucose uptake in skeletal muscle, contrasting with diminished gluconeogenesis in liver. TS exhibits hypolipidemic effect by decreasing the expressions of fatty acid synthase (FAS). Thus, antidiabetic properties of TS occurred as a result of decreased hepatic glucose production by PEPCK and G6Pase downregulation and improved insulin sensitization. Thus, amelioration of diabetic and dyslipidemic state by TS in HF-fed mice occurred by regulation of GLUT4, G6Pase, and FAS and phosphorylation of AMPK.

Role of metabolic feedback regulation in glucose production of running rats

1988 ◽  
Vol 255 (3) ◽  
pp. R400-R406
Author(s):  
J. Vissing ◽  
B. Sonne ◽  
H. Galbo
Keyword(s):  
Hepatic Glucose Production ◽  
Feedback Regulation ◽  
Glucose Production ◽  
Central Command ◽  
Feedback Mechanisms ◽  
Fed State ◽  
Hepatic Glucose ◽  
Glucose Clearance ◽  
In Series ◽  
Exercise Induced

Hepatic glucose production (Ra) was studied in phlorizin (P)- and saline (C)-infused rats running for 35 min at 21 m/min in the postabsorptive state (series I) or 18 m/min in the fed state (series II). Phlorizin-induced increase in glucose clearance would increase or not affect Ra, depending on whether metabolic feedback mechanisms or central command from central nervous system (CNS), respectively, regulate Ra during exercise. Initial exercise-induced increases in Ra were similar in P and C rats of both series, although glucose clearance was higher and plasma glucose lower, however not hypoglycemic, in P rats. After 5 min of exercise, Ra remained similar in P and C rats in series I, whereas in series II, Ra increased almost twice as much in P compared with C rats. In both series muscle glycogenolysis and lipolysis were higher in P than in C rats. The results suggest a central command regulation of Ra from CNS motor centers and that this primary setting may be modulated by metabolic feedback mechanisms. Hypoglycemia is not needed to activate metabolic feedback. A variety of substrates rather than glucose specifically is mobilized by metabolic feedback mechanisms associated with decreased glucose availability.

Upper Small Intestinal Fatty Acid Sensing Improves Glucose Tolerance Through Suppression of Hepatic Glucose Production

2015 ◽  
Vol 39 (6) ◽  
pp. 547
Author(s):  
Paige V. Bauer ◽  
Sophie C. Hamr ◽  
Frank A. Duca ◽  
Brittany A. Rasmussen ◽  
Tony K.T. Lam
Keyword(s):  
Fatty Acid ◽  
Glucose Tolerance ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hepatic Glucose ◽  
Small Intestinal ◽  
Fatty Acid Sensing

scholarly journals Systemic benefits of Gc inhibition to preserve insulin sensitivity

2020 ◽  
Author(s):  
Taiyi Kuo ◽  
Domenico Accili
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Cell Function ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
High Fat ◽  
Β Cell ◽  
Hepatic Glucose ◽  
Β Cell Function

ABSTRACTType 2 diabetes is caused by an imbalanced supply and demand of insulin. Insulin resistance and impaired β-cell function contribute to the onset of hyperglycemia. No single treatment modality can affect both aspects of diabetes pathophysiology. Thus, current treatments focus either on increasing insulin secretion (incretin mimetics, sulfonylureas) or insulin sensitivity (metformin and TZD), or reducing hyperglycemia (insulin, sglt2i). Previously, we reported that ablation of Gc, encoding a secreted protein with a primary role in vitamin D transport, improves pancreatic β-cell function in models of diet-induced insulin resistance. Here, we show that Gc ablation has systemic insulin-sensitizing effects to prevent weight gain, hyperglycemia, glucose intolerance, and lower NEFA and triglyceride in mice fed a high-fat diet. Hyperinsulinemic-euglycemic clamps show that Gc ablation protects insulin’s ability to reduce hepatic glucose production, and increases glucose uptake in skeletal muscle and adipose tissue. Moreover, acute Gc inhibition by way of adeno-associated virus encoding a short hairpin RNA to promote Gc mRNA degradation, prevents glucose intolerance caused by high fat feeding. The data suggest that Gc inhibition can provide an approach to increase insulin production in β-cells, and insulin action in peripheral tissues.RESEARCH IN CONTEXT▪ The goal was to find a therapeutic target that can improve insulin sensitivity and β-cell function simultaneously.▪ Gc ablation preserves β-cell insulin secretion ex vivo and in vivo.▪ Deletion of Gc prevents weight gain, reduces fat mass, lowers fasting glycemia, improves glucose tolerance, reduces hepatic glucose production after feeding, and increased glucose uptake in muscle and adipose.▪ Acute Gc inhibition improves glucose tolerance, which suggests that targeting Gc could provide an alternative way to treat type 2 diabetes.

Prevailing hyperglycemia is critical in the regulation of glucose metabolism during exercise in poorly controlled alloxan-diabetic dogs

2005 ◽  
Vol 98 (3) ◽  
pp. 930-939 ◽  
Author(s):  
Michael J. Christopher ◽  
Christian Rantzau ◽  
Glenn McConell ◽  
Bruce E. Kemp ◽  
Frank P. Alford
Keyword(s):  
Fatty Acid ◽  
Free Fatty Acid ◽  
Glucose Uptake ◽  
Plasma Glucose ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Plasma Free Fatty Acid ◽  
Glucose Turnover ◽  
Metabolic Clearance ◽  
Hepatic Glucose

The separate impacts of the chronic diabetic state and the prevailing hyperglycemia on plasma substrates and hormones, in vivo glucose turnover, and ex vivo skeletal muscle (SkM) during exercise were examined in the same six dogs before alloxan-induced diabetes (prealloxan) and after 4–5 wk of poorly controlled hyperglycemic diabetes (HGD) in the absence and presence of ∼300-min phlorizin-induced (glycosuria mediated) normoglycemia (NGD). For each treatment state, the ∼15-h-fasted dog underwent a primed continuous 150-min infusion of [3-3H]glucose, followed by a 30-min treadmill exercise test (∼65% maximal oxygen capacity), with SkM biopsies taken from the thigh (vastus lateralis) before and after exercise. In the HGD and NGD states, preexercise hepatic glucose production rose by 130 and 160%, and the metabolic clearance rate of glucose (MCRg) fell by 70 and 37%, respectively, compared with the corresponding prealloxan state, but the rates of glucose uptake into peripheral tissues (Rdtissue) and total glycolysis (GF) were unchanged, despite an increased availability of plasma free fatty acid in the NGD state. Exercise-induced increments in hepatic glucose production, Rdtissue, and plasma-derived GF were severely blunted by ∼30–50% in the NGD state, but increments in MCRg remained markedly reduced by ∼70–75% in both diabetic states. SkM intracellular glucose concentrations were significantly elevated only in the HGD state. Although Rdtissue during exercise in the diabetic states correlated positively with preexercise plasma glucose and insulin and GF and negatively with preexercise plasma free fatty acid, stepwise regression analysis revealed that an individual's preexercise glucose and GF accounted for 88% of Rdtissue during exercise. In conclusion, the prevailing hyperglycemia in poorly controlled diabetes is critical in maintaining a sufficient supply of plasma glucose for SkM glucose uptake during exercise. During phlorizin-induced NGD, increments in both Rdtissue and GF are impaired due to a diminished fuel supply from plasma glucose and a sustained reduction in increments of MCRg.

Glucose metabolic adaptations in the intrauterine growth-restricted adult female rat offspring

2006 ◽  
Vol 290 (6) ◽  
pp. E1218-E1226 ◽  
Author(s):  
Meena Garg ◽  
Manikkavasagar Thamotharan ◽  
Lisa Rogers ◽  
Sara Bassilian ◽  
W. N. Paul Lee ◽  
...  
Keyword(s):  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Glucose Disposal ◽  
Nutrient Restriction ◽  
Female Rat ◽  
Intrauterine Growth ◽  
Rat Offspring ◽  
Metabolic Adaptations ◽  
Hepatic Glucose ◽  
Glucose Clearance

We studied glucose metabolic adaptations in the intrauterine growth-restricted (IUGR) rat offspring to decipher glucose homeostasis in metabolic programming. Glucose futile cycling (GFC), which is altered when there is imbalance between glucose production and utilization, was studied during a glucose tolerance test (GTT) in 2-day-old ( n = 8), 2-mo-old ( n = 22), and 15-mo-old ( n = 22) female rat offspring. The IUGR rats exposed to either prenatal (CM/SP, n = 5 per age), postnatal (SM/CP, n = 6), or pre- and postnatal (SM/SP, n = 6) nutrient restriction were compared with age-matched controls (CM/CP, n = 5). At 2 days, IUGR pups (SP) were smaller and glucose intolerant and had increased hepatic glucose production and increased glucose disposal ( P < 0.01) compared with controls (CP). At 2 mo, the GTT, glucose clearance, and GFC did not change. However, a decline in hepatic glucose-6-phosphatase ( P < 0.05) and fructose-1,6-biphosphatase ( P < 0.05) enzyme activities in the IUGR offspring was detected. At 15 mo, prenatal nutrient restriction (CM/SP) resulted in greater weight gain ( P < 0.01) and hyperinsulinemia ( P < 0.001) compared with postnatal nutrient restriction (SM/CP). A decline in GFC in the face of a normal GTT occurred in both the prenatal (CM/SP, P < 0.01) and postnatal calorie (SM/CP, P < 0.03) and growth-restricted offspring. The IUGR offspring with pre- and postnatal nutrient restriction (SM/SP) were smaller, hypoinsulinemic ( P < 0.03), and hypoleptinemic ( P < 0.03), with no change in GTT, hepatic glucose production, GFC, or glucose clearance. We conclude that there is pre- and postnatal programming that affects the postnatal compensatory adaptation of GFC and disposal initiated by changes in circulating insulin concentrations, thereby determining hepatic insulin sensitivity in a phenotype-specific manner.

Increasing fructose 2,6-bisphosphate overcomes hepatic insulin resistance of type 2 diabetes

2002 ◽  
Vol 282 (1) ◽  
pp. E38-E45 ◽  
Author(s):  
Chaodong Wu ◽  
David A. Okar ◽  
Christopher B. Newgard ◽  
Alex J. Lange
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hepatic Insulin Resistance ◽  
Insulin Resistant ◽  
Kk Mice ◽  
Hepatic Glucose

Hepatic glucose production is increased as a metabolic consequence of insulin resistance in type 2 diabetes. Because fructose 2,6-bisphosphate is an important regulator of hepatic glucose production, we used adenovirus-mediated enzyme overexpression to increase hepatic fructose 2,6-bisphosphate to determine if the hyperglycemia in KK mice, polygenic models of type 2 diabetes, could be ameliorated by reduction of hepatic glucose production. Seven days after treatment with virus encoding a mutant 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase designed to increase fructose 2,6-bisphosphate levels, plasma glucose, lipids, and insulin were significantly reduced in KK/H1J and KK.Cg-Ay/J mice. Moreover, high fructose 2,6-bisphosphate levels downregulated glucose-6-phosphatase and upregulated glucokinase gene expression, thereby reversing the insulin-resistant pattern of hepatic gene expression of these two key glucose-metabolic enzymes. The increased hepatic fructose 2,6-bisphosphate also reduced adiposity in both KK mice. These results clearly indicate that increasing hepatic fructose 2,6-bisphosphate overcomes the impairment of insulin in suppressing hepatic glucose production, and it provides a potential therapy for type 2 diabetes.

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