Insulin resistance in the GK rat: decreased receptor number but normal kinase activity in liver

1993 ◽  
Vol 265 (5) ◽  
pp. E807-E813 ◽  
Author(s):  
S. Bisbis ◽  
D. Bailbe ◽  
M. A. Tormo ◽  
F. Picarel-Blanchot ◽  
M. Derouet ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Utilization ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Gk Rat ◽  
Peripheral Tissues ◽  
Relative Index ◽  
Gk Rats ◽  
Euglycemic Clamp

We have previously shown that the glucose intolerance and the hyperglycemic state in the GK rat, a new spontaneous model of non-insulin-dependent (type II) diabetes without obesity, are partly accounted for by an alteration of the pancreatic B cell response. On the other hand, the hyperglycemic-hyperinsulinemic pattern in these rats suggests a decrease of response to insulin in the basal state. In the present study, in vivo insulin action was assessed in 8-wk-old GK females at basal and submaximal (euglycemic clamp) insulin levels. Overall glucose utilization (OGU), individual tissue glucose utilization (ITGU, in vivo uptake of the glucose analogue 2-deoxy-D-glucose as the relative index of glucose metabolism), as well as hepatic glucose production (GP) and liver insulin receptor properties were determined under these two conditions. The basal OGU was significantly higher in the GK females, compared with that in control Wistar females. The hyperinsulinemic-euglycemic clamp experiments indicated that peripheral insulin resistance was installed at 8 wk of age in the GK females because 1) OGU was significantly lower and 2) in some peripheral tissues (epitrochlearis muscle, periovarian, and inguinal white adipose tissues), but not all, ITGU was significantly lower compared with corresponding ITGU in control rats. In the basal state GP was significantly higher in the GK rats. At submaximal hyperinsulinemia (and euglycemia), it was less effectively suppressed than in the controls, thus demonstrating liver insulin resistance. Under both basal state and clamp condition, binding of 125I-A14-insulin to liver membranes of GK rats was significantly decreased by 20-30%.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of norepinephrine infusion on in vivo insulin sensitivity and responsiveness

1990 ◽  
Vol 259 (2) ◽  
pp. E210-E215 ◽  
Author(s):  
J. R. Lupien ◽  
M. F. Hirshman ◽  
E. S. Horton
Keyword(s):  
Insulin Sensitivity ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Glucose Disposal ◽  
Glucose Turnover ◽  
Adrenergic Blockade ◽  
Sprague Dawley ◽  
Euglycemic Hyperinsulinemic Clamp ◽  
Peripheral Tissues

The effect of a continuous infusion of norepinephrine (NE) on glucose disposal in vivo was examined in conscious restrained rats using the euglycemic-hyperinsulinemic clamp technique. NE, 1,000 micrograms.kg-1.day-1 (130 nmol.kg-1.h-1) or vehicle (CO) was infused for 10 days in adult male Sprague-Dawley rats using subcutaneously implanted osmotic minipumps. Body weight and food intake were similar in both groups of animals throughout the study. Fasting basal plasma glucose and insulin concentrations were similar in both groups. However, basal hepatic glucose production (HGP) was increased by NE treatment (9.03 +/- 0.63 vs. 13.20 +/- 1.15 mg.kg-1.min-1, P less than 0.05, CO vs. NE, respectively). Insulin infusions of 2, 6, and 200 mU.kg-1.min-1 suppressed HGP to the same degree in both groups. During 2, 6, and 200 mU.kg-1.h-1 insulin infusions the glucose disposal rate was 65, 60, and 13% greater in NE-treated animals than in controls. Acute beta-adrenergic blockade with propranolol infused at 405 nmol.kg-1.h-1 during the glucose clamps did not normalize glucose disposal. These results demonstrate that chronic NE infusion is associated with increased basal glucose turnover and increased insulin sensitivity of peripheral tissues.

scholarly journals The tumor suppressor TMEM127 regulates insulin sensitivity in a tissue-specific manner

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Subramanya Srikantan ◽  
Yilun Deng ◽  
Zi-Ming Cheng ◽  
Anqi Luo ◽  
Yuejuan Qin ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Tumor Suppressor ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Suppressor Gene ◽  
Nutrient Sensing ◽  
Whole Body ◽  
Insulin Sensitizer

Abstract Understanding the molecular components of insulin signaling is relevant to effectively manage insulin resistance. We investigated the phenotype of the TMEM127 tumor suppressor gene deficiency in vivo. Whole-body Tmem127 knockout mice have decreased adiposity and maintain insulin sensitivity, low hepatic fat deposition and peripheral glucose clearance after a high-fat diet. Liver-specific and adipose-specific Tmem127 deletion partially overlap global Tmem127 loss: liver Tmem127 promotes hepatic gluconeogenesis and inhibits peripheral glucose uptake, while adipose Tmem127 downregulates adipogenesis and hepatic glucose production. mTORC2 is activated in TMEM127-deficient hepatocytes suggesting that it interacts with TMEM127 to control insulin sensitivity. Murine hepatic Tmem127 expression is increased in insulin-resistant states and is reversed by diet or the insulin sensitizer pioglitazone. Importantly, human liver TMEM127 expression correlates with steatohepatitis and insulin resistance. Our results suggest that besides tumor suppression activities, TMEM127 is a nutrient-sensing component of glucose/lipid homeostasis and may be a target in insulin resistance.

Perturbation of glucose flux in the liver by decreasing F26P2 levels causes hepatic insulin resistance and hyperglycemia

2006 ◽  
Vol 291 (3) ◽  
pp. E536-E543 ◽  
Author(s):  
Chaodong Wu ◽  
Salmaan A. Khan ◽  
Li-Jen Peng ◽  
Honggui Li ◽  
Steven G. Carmella ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hepatic Insulin Resistance ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose Flux ◽  
Hepatic Glucose

Hepatic insulin resistance is one of the characteristics of type 2 diabetes and contributes to the development of hyperglycemia. How changes in hepatic glucose flux lead to insulin resistance is not clearly defined. We determined the effects of decreasing the levels of hepatic fructose 2,6-bisphosphate (F26P2), a key regulator of glucose metabolism, on hepatic glucose flux in the normal 129J mice. Upon adenoviral overexpression of a kinase activity-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, the enzyme that determines F26P2 level, hepatic F26P2 levels were decreased twofold compared with those of control virus-treated mice in basal state. In addition, under hyperinsulinemic conditions, hepatic F26P2 levels were much lower than those of the control. The decrease in F26P2 leads to the elevation of basal and insulin-suppressed hepatic glucose production. Also, the efficiency of insulin to suppress hepatic glucose production was decreased (63.3 vs. 95.5% suppression of the control). At the molecular level, a decrease in insulin-stimulated Akt phosphorylation was consistent with hepatic insulin resistance. In the low hepatic F26P2 states, increases in both gluconeogenesis and glycogenolysis in the liver are responsible for elevations of hepatic glucose production and thereby contribute to the development of hyperglycemia. Additionally, the increased hepatic gluconeogenesis was associated with the elevated mRNA levels of peroxisome proliferator-activated receptor-γ coactivator-1α and phospho enolpyruvate carboxykinase. This study provides the first in vivo demonstration showing that decreasing hepatic F26P2 levels leads to increased gluconeogenesis in the liver. Taken together, the present study demonstrates that perturbation of glucose flux in the liver plays a predominant role in the development of a diabetic phenotype, as characterized by hepatic insulin resistance.

Peripheral and hepatic resistance to insulin and hepatic resistance to glucagon in uraemic subjects

1988 ◽  
Vol 118 (1) ◽  
pp. 125-134 ◽  
Author(s):  
Ole Schmitz
Keyword(s):  
Insulin Resistance ◽  
Insulin Infusion ◽  
Serum Insulin ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Hepatic Insulin Resistance ◽  
Glucose Disposal ◽  
Peripheral Tissues ◽  
Endogenous Glucose

Abstract. To characterize endogenous glucose production in uraemia, nondialyzed uraemic patients and controls were exposed to two major modulating hormones, insulin and glucagon. Nineteen uraemic and 15 healthy subjects underwent either a 2-step (insulin infusion rates: 0.45 and 1.0 mU·kg−1·min−1) or a 3-step (insulin infusion rates: 0.1, 0.2 and 0.3 mU·kg−1·min−1 sequential euglycaemic insulin clamp. Average steady state serum insulin concentrations were almost identical during all five infusion rates in uraemic patients (16,22, 26, 31 and 66 mU/l) and controls (15, 19, 24, 33 and 68 mU/l). At all steps, insulin infusion was accompanied by significantly lower glucose disposal rates ([3−3H]glucose) in uraemic patients compared with controls (P < 0.05 or less). Moreover, the restraining potency of insulin on endogenous glucose production was much more prominent in healthy than in uraemic subjects at the lowest three infusion rates (0.6 ± 1.0 versus 1.4 ± 0.3 (mean ± 1 sd), −0.3 ± 0.7 versus 0.7 ± 0.3, and −1.1 ± 0.7 versus 0.2 ± 0.6 mg·kg−1·min−1; P < 0.05, P < 0.01 and P < 0.01, respectively), implying a shift to the right of the dose-response curve in uraemia. In contrast, basal values were comparable (2.4 ± 0.3 versus 2.2 ± 0.6 mg·kg−1·min−1) as the difference vanished at higher infusion rates, i.e. peripheral insulinaemia above ≈30 mU/l. Another 7 uraemic patients and 7 controls were infused with glucagon at constant rates of 4 or 6 ng·kg−1·min−1, respectively, for 210 min concomitant with somatostatin (125 μg/h) and tritiated glucose. The ability of glucagon to elevate plasma glucose was markedly attenuated in uraemic patients compared with controls during the initial 60 min of glucagon exposure. This difference was entirely due to diminished hepatic glucose production (3.5 ± 0.8 versus 4.8 ± 1.0 mg·kg−1·min−1; P < 0.05). In conclusion, in addition to insulin resistance in peripheral tissues, uraemia is also associated with hepatic insulin resistance. Furthermore, glucagon challenge implies impaired early endogenous glucose release in uraemia suggesting a superimposed hepatic resistance to glucagon.

Free fatty acids increase basal hepatic glucose production and induce hepatic insulin resistance at different sites

2003 ◽  
Vol 284 (2) ◽  
pp. E281-E290 ◽  
Author(s):  
Tony K. T. Lam ◽  
Gérald Van de Werve ◽  
Adria Giacca
Keyword(s):  
Insulin Resistance ◽  
Phosphatase Activity ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Fatty Acyl ◽  
Hepatic Insulin Resistance ◽  
P Content ◽  
Hepatic Glucose ◽  
Fasted Rats

To investigate the sites of the free fatty acid (FFA) effects to increase basal hepatic glucose production and to impair hepatic insulin action, we performed 2-h and 7-h Intralipid + heparin (IH) and saline infusions in the basal fasting state and during hyperinsulinemic clamps in overnight-fasted rats. We measured endogenous glucose production (EGP), total glucose output (TGO, the flux through glucose-6-phosphatase), glucose cycling (GC, index of flux through glucokinase = TGO − EGP), hepatic glucose 6-phosphate (G-6- P) content, and hepatic glucose-6-phosphatase and glucokinase activities. Plasma FFA levels were elevated about threefold by IH. In the basal state, IH increased TGO, in vivo glucose-6-phosphatase activity (TGO/G-6- P), and EGP ( P < 0.001). During the clamp compared with the basal experiments, 2-h insulin infusion increased GC and in vivo glucokinase activity (GC/TGO; P < 0.05) and suppressed EGP ( P< 0.05) but failed to significantly affect TGO and in vivo glucose-6-phosphatase activity. IH decreased the ability of insulin to increase GC and in vivo glucokinase activity ( P < 0.01), and at 7 h, it also decreased the ability of insulin to suppress EGP ( P < 0.001). G-6- P content was comparable in all groups. In vivo glucose-6-phosphatase and glucokinase activities did not correspond to their in vitro activities as determined in liver tissue, suggesting that stable changes in enzyme activity were not responsible for the FFA effects. The data suggest that, in overnight-fasted rats, FFA increased basal EGP and induced hepatic insulin resistance at different sites. 1) FFA increased basal EGP through an increase in TGO and in vivo glucose-6-phosphatase activity, presumably due to a stimulatory allosteric effect of fatty acyl-CoA on glucose-6-phosphatase. 2) FFA induced hepatic insulin resistance (decreased the ability of insulin to suppress EGP) through an impairment of insulin's ability to increase GC and in vivo glucokinase activity, presumably due to an inhibitory allosteric effect of fatty acyl-CoA on glucokinase and/or an impairment in glucokinase translocation.

scholarly journals Resveratrol prevents insulin resistance caused by short-term elevation of free fatty acids in vivo

2015 ◽  
Vol 40 (11) ◽  
pp. 1129-1136 ◽  
Author(s):  
Sandra Pereira ◽  
Edward Park ◽  
Jessy Moore ◽  
Brandon Faubert ◽  
Danna M. Breen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Free Fatty Acids ◽  
Glucose Utilization ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Serine Phosphorylation ◽  
Peripheral Insulin Resistance ◽  
Induce Insulin Resistance

Elevated levels of plasma free fatty acids (FFA), which are commonly found in obesity, induce insulin resistance. FFA activate protein kinases including the proinflammatory IκBα kinase β (IKKβ), leading to serine phosphorylation of insulin receptor substrate 1 (IRS-1) and impaired insulin signaling. To test whether resveratrol, a polyphenol found in red wine, prevents FFA-induced insulin resistance, we used a hyperinsulinemic-euglycemic clamp with a tracer to assess hepatic and peripheral insulin sensitivity in overnight-fasted Wistar rats infused for 7 h with saline, Intralipid plus 20 U·mL−1 heparin (IH; triglyceride emulsion that elevates FFA levels in vivo; 5.5 μL·min−1) with or without resveratrol (3 mg·kg−1·h−1), or resveratrol alone. Infusion of IH significantly decreased glucose infusion rate (GIR; P < 0.05) and peripheral glucose utilization (P < 0.05) and increased endogenous glucose production (EGP; P < 0.05) during the clamp compared with saline infusion. Resveratrol co-infusion, however, completely prevented the effects induced by IH infusion: it prevented the decreases in GIR (P < 0.05 vs. IH), peripheral glucose utilization (P < 0.05 vs. IH), and insulin-induced suppression of EGP (P < 0.05 vs. IH). Resveratrol alone had no effect. Furthermore, IH infusion increased serine (307) phosphorylation of IRS-1 in soleus muscle (∼30-fold, P < 0.001), decreased total IRS-1 levels, and decreased IκBα content, consistent with activation of IKKβ. Importantly, all of these effects were abolished by resveratrol (P < 0.05 vs. IH). These results suggest that resveratrol prevents FFA-induced hepatic and peripheral insulin resistance and, therefore, may help mitigate the health consequences of obesity.

Effect of charge on hepatic specific nature of vesicle encapsulated insulin in conscious dogs

1986 ◽  
Vol 251 (5) ◽  
pp. E591-E596 ◽  
Author(s):  
R. S. Spangler ◽  
K. C. Triebwasser ◽  
M. L. Wilson
Keyword(s):  
Glucose Utilization ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Conscious Dogs ◽  
Therapeutic Window ◽  
Specific Nature ◽  
Comparable Amount ◽  
Peripheral Tissues ◽  
Hepatic Glucose ◽  
Dose Levels

Positively [(+)-VEI] and negatively [(-)-VEI] charged formulations of vesicle encapsulated insulin (VEI) were compared with insulin on the basis of their ability to suppress hepatic glucose production (hepatic Ra) and stimulate glucose utilization (Rd) in conscious dogs. Our results indicate that (-)-VEI and insulin have an equivalent capacity to suppress hepatic glucose production at dose levels of 0.2, 1.2, and 2.4 mU X kg-1 X min-1. (+)-VEI is less effective at suppressing hepatic Ra than both insulin and (-)-VEI at dose levels of 1.2 and 2.4 mU X kg-1 X min-1. Both (+)-VEI and (-)-VEI induced significantly less glucose utilization than a comparable amount of insulin at dose levels of 1.2 and 2.4 mU X kg-1 X min-1. The amount of glucose utilization stimulated by (+)-VEI was significantly less than that induced by insulin at 0.6 mU X kg-1 X min-1. This difference was not evident with (-)-VEI. These results suggest that the insulin contained in (+)-VEI is less bioavailable than that contained in (-)-VEI. This difference in bioavailability is believed to be the result of greater serum stability of (+)-VEI vesicles when compared with that of (-)-VEI. In conclusion, both (+)-VEI and (-)-VEI have the capacity to shield encapsulated insulin from interacting with peripheral tissues and deliver insulin selectively to the liver. Both formulations afford one an opportunity to expand the therapeutic window for hepatically active compounds where their utility is limited by systemic toxicity.

Impaired insulin secretion and excessive hepatic glucose production are both early events in the diabetic GK rat

1996 ◽  
Vol 271 (4) ◽  
pp. E755-E762 ◽  
Author(s):  
F. Picarel-Blanchot ◽  
C. Berthelier ◽  
D. Bailbe ◽  
B. Portha
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Beta Cell ◽  
Insulin Release ◽  
Glucose Utilization ◽  
Glucose Production ◽  
Gk Rat ◽  
Adipose Tissues ◽  
Hepatic Glucose ◽  
Insulin Dependent

Adult Goto-Kakisaki Wistar (GK) rats exhibit a spontaneous non-insulin-dependent diabetes characterized by impaired glucose-induced insulin secretion, decreased beta-cell mass, hepatic glucose overproduction, and moderate insulin resistance in muscles and adipose tissues. To elucidate the pathogenesis of hyperglycemia in this animal model, we have studied insulin secretion and insulin action in 4-wk-old GK pups, just before weaning. In the postabsorptive state, their basal plasma glucose level was elevated (P < 0.001), and their tolerance to intravenous glucose was impaired. Their kinetics of insulin release in response to glucose was impaired, with a low acute phase of insulin release in vivo and in vitro (perfused pancreas). Basal glucose production was increased in the GK pups by 40% (P < 0.05). During euglycemic clamp performed at submaximal hyperinsulinemia, suppression of liver glucose production was less effective (P < 0.01) in the GK rats, whereas their overall glucose utilization was similar to that of the control group. This was correlated with a normal insulin-stimulated glucose utilization by epitrochlearis, soleus, and extensor digitorum longus muscles, diaphragm, and white adipose tissues. These data give body to the primacy of the beta-cell defects in the etiology of non-insulin-dependent diabetes mellitus in the GK rat. They also highlight a possible primary role of the liver defect. Peripheral insulin resistance does not contribute to the development of postnatal glucose intolerance in this diabetes model.

scholarly journals Development of insulin-sensitivity at weaning in the rat. Role of the nutritional transition

1988 ◽  
Vol 251 (3) ◽  
pp. 685-690 ◽  
Author(s):  
T Issad ◽  
C Coupé ◽  
M Pastor-Anglada ◽  
P Ferré ◽  
J Girard
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Clearance Rate ◽  
Glucose Utilization ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Glucose Turnover ◽  
Turnover Rates ◽  
Suckling Rats ◽  
Glucose Clearance

This study was undertaken to determine the factors involved in the development of insulin-sensitivity at weaning. Glucose kinetics were studied in suckling rats and in rats weaned on to a high-carbohydrate (HC) or a high-fat (HF) diet, in the basal state and during euglycaemic-hyperinsulinaemic-clamp studies. These studies were coupled with the 2-deoxyglucose technique, allowing a measure of glucose utilization by individual tissues. In the basal state, the glycaemia was higher in HF-weaned rats (124 +/- 4 mg/dl) than in suckling (109 +/- 1 mg/dl) and HC-weaned rats (101 +/- 3 mg/dl). Glucose turnover rates were similar in the three groups of animals (14 mg/min per kg). Nevertheless, basal metabolic glucose clearance rate was 20% lower in HF-weaned rats than in the other groups. During the euglycaemic-hyperinsulinaemic experiments, hepatic glucose production was suppressed by 90% in HC-weaned rats, whereas it remained at 40% of basal value in suckling and HF-weaned rats, indicating an insulin resistance of liver of these animals. Glucose clearance rate during the clamp was 18.3 +/- 0.9 ml/min per kg in suckling rats, whereas it was 35.3 +/- 1.2 ml/min per kg in HC-weaned rats and 27.8 +/- 1.1 ml/min per kg in HF-weaned rats, indicating an insulin resistance of glucose utilization in suckling, and to a lower extent, in HF-weaned rats. The deoxyglucose technique showed that peripheral insulin resistance was localized in muscles and white adipose tissue of suckling and HF-weaned rats. These results indicate that the switch from milk to a HC diet is an important determinant of the development of insulin-sensitivity at weaning in the rat.

Sign in / Sign up

Export Citation Format

Share Document