Temporal changes in insulin resistance and secretion in 24-h-fasted conscious pregnant rats

1993 ◽  
Vol 265 (6) ◽  
pp. E845-E851 ◽  
Author(s):  
G. Rossi ◽  
R. S. Sherwin ◽  
A. S. Penzias ◽  
P. Lapaczewski ◽  
R. J. Jacob ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Action ◽  
Insulin Dose ◽  
Glucose Production ◽  
Late Pregnancy ◽  
Hepatic Insulin Resistance ◽  
Pregnant Rats ◽  
Hyperglycemic Clamp ◽  
Peripheral Insulin Resistance ◽  
Insulin Responses

To determine the temporal sequence of pregnancy-induced changes in insulin action and secretion, awake midpregnant (11-12 days) and late pregnant (19-20 days) rats underwent a two-step euglycemic hyperinsulinemic or a hyperglycemic clamp study after a 24-h fast. During euglycemia, insulin-stimulated increments in glucose uptake and clearance in midpregnant rats were reduced by 60-70% at the lower dose (insulin approximately 360 pM) and by 20-30% at the higher dose (insulin approximately 1,750 pM; P < 0.01 vs. virgin controls). Insulin action was also diminished in late pregnant rats. However, the magnitude of resistance did not increase. Insulin-mediated suppression of glucose production was only minimally impaired in midpregnancy. In contrast, glucose production was virtually unchanged in late pregnancy, even at the highest insulin dose. During hyperglycemia, insulin responses in late pregnancy were markedly increased 5-fold above controls and 2.5-fold above midpregnant rats (P < 0.05). We conclude that rat pregnancy is characterized by the early appearance of peripheral insulin resistance. As pregnancy progresses toward term, marked hepatic insulin resistance and insulin hypersecretion develop, whereas peripheral insulin resistance demonstrates negligible changes. These data imply that insulin hypersecretion during late pregnancy is most closely linked to hepatic insulin resistance, at least in 24-h-fasted animals.

Lowering plasma free fatty acid levels improves insulin action in conscious pregnant rabbits

1993 ◽  
Vol 264 (4) ◽  
pp. E576-E582 ◽  
Author(s):  
M. Gilbert ◽  
S. Basile ◽  
A. Baudelin ◽  
M. C. Pere
Keyword(s):  
Insulin Resistance ◽  
Insulin Action ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Late Pregnancy ◽  
Plasma Free Fatty Acid ◽  
Glucose Disposal ◽  
Hepatic Glucose ◽  
Total Glucose ◽  
Control Study

Acute elevation in plasma free fatty acid (FFA) levels in nonpregnant rabbits simulates some aspects of insulin resistance observed in late pregnancy. The aim of this study was therefore to evaluate whether lowered FFA induced by nicotinic acid (NA) infusion can improve insulin action in pregnant rabbits. To assess insulin sensitivity we applied euglycemic hyperinsulinemic clamp without (control study) or with concomitant NA infusion (NA study; infusion started 150 min before the glucose clamp) in conscious virgin and pregnant rabbits after an 18-h fast. A primed constant infusion of [3-3H]glucose was used to measure total glucose disposal and hepatic glucose production. Hyperinsulinemia, in association with NA infusion (NA study) brings about a significantly greater stimulation of total glucose disposal in both pregnant (approximately 30%) and nonpregnant (approximately 35%) rabbits compared with the control study. A more pronounced inhibition of hepatic glucose production occurred in NA study in pregnant rabbits (approximately 30 vs. approximately 10%) but it did not reach a statistical significance, whereas there was a total inhibition in nonpregnant rabbits. We conclude that acute decrease in plasma FFA levels mainly improves insulin action at the site of glucose utilization. These results therefore suggest that elevated FFA would contribute to the peripheral insulin resistance in late pregnancy.

Influence of growth hormone on glucose-glucose 6-phosphate cycle and insulin action in normal humans

1992 ◽  
Vol 263 (5) ◽  
pp. E980-E987 ◽  
Author(s):  
R. D. Neely ◽  
D. P. Rooney ◽  
P. M. Bell ◽  
N. P. Bell ◽  
B. Sheridan ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Growth Hormone ◽  
Insulin Action ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Hepatic Insulin Resistance ◽  
Glucose Disposal ◽  
Impaired Insulin ◽  
Increased Activity ◽  
P Cycle

Increased activity of the hepatic glucose-glucose 6-phosphate (G/G-6-P) cycle is associated with hepatic and peripheral insulin resistance in acromegaly. To determine whether a similar association occurs after short-term growth hormone (GH) elevation within the physiological range, two-step euglycemic hyperinsulinemic clamps were performed in normal human males after 12-h GH (2.2 ng.kg-1 x h-1) and control infusions. G/G-6-P cycle activity and endogenous glucose production (EGP) were determined by [2-3H]- and [6-3H]-glucose using labeled exogenous glucose infusions and selective enzymatic detritiation. GH increased levels of circulating lipid intermediates despite a twofold increase in basal insulin (P < 0.005), but plasma glucose, EGP, and G/G-6-P cycle activity were unchanged. GH impaired insulin suppression of EGP and lipid intermediates and impaired insulin stimulation of glucose disposal, but G/G-6-P cycle activity was unchanged. We conclude that increased activity of the G/G-6-P cycle does not contribute to the hepatic insulin resistance induced by GH under these conditions but that changes in fatty acid metabolism may be partly responsible for the impairment in hepatic and peripheral insulin action.

Impairment of insulin action on peripheral glucose uptake and hepatic glucose production in tumor-bearing rats

1993 ◽  
Vol 265 (2) ◽  
pp. R356-R364 ◽  
Author(s):  
C. H. Lang ◽  
N. Skrepnik ◽  
C. Dobrescu ◽  
A. H. Burns
Keyword(s):  
Insulin Resistance ◽  
Glucose Uptake ◽  
Insulin Action ◽  
Glucose Production ◽  
Tumor Burden ◽  
Hepatic Insulin Resistance ◽  
Whole Body ◽  
Glucose Turnover ◽  
Tumor Bearing ◽  
Time Point

The present study was performed to determine the time-course for the development of peripheral and hepatic insulin resistance in rats as a result of an increasing tumor burden. Animals were inoculated with Yoshida ascites hepatoma, and studies were conducted during the early phase of tumor growth (day 4) at which time there was no change in food intake and at a later time point (day 8) when the tumor burden was increased and rats demonstrated anorexia. In vivo insulin action was accessed under euglycemic hyperinsulinemic conditions, in which insulin was infused at rates sufficient to produce arterial insulin levels that represent high physiological (3.5 ng/ml) or maximally stimulating values (180 ng/ml). On day 4, tumor-bearing (TB) rats were euglycemic, and whole body glucose turnover was elevated 32%. Insulin-mediated glucose uptake (IMGU) in TB rats was similar to control values at the low insulin infusion rate but reduced by 53% under maximally stimulating conditions. The insulin-induced suppression of glucose production was similar in TB and control animals at this time point. In contrast, on day 8, TB rats were hypoglycemic and glucose turnover was reduced 35%. The impairment in IMGU was more severe than seen earlier, with glucose uptake being reduced 39 and 61% at both levels of hyperinsulinemia. At this time point, the ability of insulin to inhibit glucose production was also impaired. These results indicate that the insulin resistance induced by the Yoshida hepatoma was manifested initially by a reduction in IMGU by peripheral tissues. As the tumor burden increased peripheral insulin resistance became more severe and an impairment in hepatic insulin action was observed.

scholarly journals Role of 17beta-estradiol and/or progesterone on insulin sensitivity in the rat: implications during pregnancy

2000 ◽  
Vol 166 (2) ◽  
pp. 283-291 ◽  
Author(s):  
C Gonzalez ◽  
A Alonso ◽  
N Alvarez ◽  
F Diaz ◽  
M Martinez ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Insulin Action ◽  
Plasma Concentrations ◽  
Late Pregnancy ◽  
Ovariectomized Rats ◽  
Euglycemic Hyperinsulinemic Clamp ◽  
Pregnant Rats ◽  
Insulin Resistant

The mechanism for the development of insulin resistance in normal pregnancy is complex and is associated with serum levels of both progesterone and 17beta-estradiol. However, it remains unclear whether estrogens alone or progestins alone can cause insulin resistance, or whether it is a combination of both which produces this effect. We attempted to determine the role played by progesterone and/or 17beta-estradiol on the phenomena of sensitivity to insulin action that take place during pregnancy in the rat. Ovariectomized rats were treated with different doses of progesterone and/or 17beta-estradiol in order to simulate the plasma levels in normal pregnant rats. A euglycemic/hyperinsulinemic clamp was used to measure insulin sensitivity. At days 6 and 11, vehicle (V)- and progesterone (P)-treated groups were more insulin resistant than 17beta-estradiol (E)- and 17beta-estradiol+progesterone (EP)-treated groups. Nevertheless, at day 16, the V, EP and E groups were more resistant to insulin action than the P group. On the other hand, the V, EP and E groups were more insulin resistant at day 16 than at day 6, whereas the P group was more insulin resistant at day 6 than at day 16. Our results seem to suggest that the absence of female steroid hormones gives rise to a decreased insulin sensitivity. The rise in insulin sensitivity during early pregnancy, when the plasma concentrations of 17beta-estradiol and progesterone are low, could be due to 17beta-estradiol. However, during late pregnancy when the plasma concentrations of 17beta-estradiol and progesterone are high, the role of 17beta-estradiol could be to antagonize the effect of progesterone, diminishing insulin sensitivity.

scholarly journals Metformin attenuates olanzapine-induced hepatic, but not peripheral insulin resistance

2015 ◽  
Vol 227 (2) ◽  
pp. 71-81 ◽  
Author(s):  
Gary J Remington ◽  
Celine Teo ◽  
Virginia Wilson ◽  
Araba Chintoh ◽  
Melanie Guenette ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Hepatic Glucose Production ◽  
Early Time ◽  
Glucose Production ◽  
Serum Lactate ◽  
Hepatic Insulin Resistance ◽  
Whole Body ◽  
Treatment Groups ◽  
Peripheral Insulin Resistance ◽  
Therapeutic Doses

Antipsychotics (APs) are linked to diabetes, even without weight gain. Whether anti-diabetic drugs are efficacious in reversing the direct effects of APs on glucose pathways is largely undetermined. We tested two metformin (Met) doses to prevent impairments seen following a dose of olanzapine (Ola) (3 mg/kg); glucokinetics were measured using the hyperinsulinemic-euglycemic clamp (HIEC). Met (150 mg/kg; n=13, or 400 mg/kg; n=11) or vehicle (Veh) (n=11) was administered through gavage preceding an overnight fast, followed by a second dose prior to the HIEC. Eleven additional animals were gavaged with Veh and received a Veh injection during the HIEC (Veh/Veh); all others received Ola. Basal glucose was similar across treatment groups. The Met 400 group had significantly greater glucose appearance (Ra) in the basal period (i.e., before Ola, or hyperinsulinemia) vs other groups. During hyperinsulinemia, glucose infusion rate (GINF) to maintain euglycemia (reflective of whole-body insulin sensitivity) was higher in Veh/Veh vs other groups. Met 150/Ola animals demonstrated increased GINF relative to Veh/Ola during early time points of the HIEC. Glucose utilization during hyperinsulinemia, relative to basal conditions, was significantly higher in Veh/Veh vs other groups. The change in hepatic glucose production (HGP) from basal to hyperinsulinemia demonstrated significantly greater decreases in Veh/Veh and Met 150/Ola groups vs Veh/Ola. Given the increase in basal Ra with Met 400, we measured serum lactate (substrate for HGP), finding increased levels in Met 400 vs Veh and Met 150. In conclusion, Met attenuates hepatic insulin resistance observed with acute Ola administration, but fails to improve peripheral insulin resistance. Use of supra-therapeutic doses of Met may mask metabolic benefits by increasing lactate.

scholarly journals CaMKIV limits metabolic damage through induction of hepatic autophagy by CREB in obese mice

2020 ◽  
Vol 244 (2) ◽  
pp. 353-367 ◽  
Author(s):  
Jiali Liu ◽  
Yue Li ◽  
Xiaoyan Zhou ◽  
Xi Zhang ◽  
Hao Meng ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Inflammatory Response ◽  
Mitochondrial Dysfunction ◽  
High Fat Diet ◽  
Insulin Action ◽  
Hepatic Insulin Resistance ◽  
Obese Mice ◽  
High Fat ◽  
Impaired Insulin

High-fat diet (HFD) not only induces insulin resistance in liver, but also causes autophagic imbalance and metabolic disorders, increases chronic inflammatory response and induces mitochondrial dysfunction. Calcium/calmodulin-dependent protein kinase IV (CaMKIV) has recently emerged as an important regulator of glucose metabolism and skeletal muscle insulin action. Its activation has been involved in the improvement of hepatic and adipose insulin action. But the underlying mechanism is not fully understood. In the present study, we aimed to address the direct effects of CaMKIV in vivo and to evaluate the potential interaction of impaired insulin sensitivity and autophagic disorders in hepatic insulin resistance. Our results indicated obese mice receiving CaMKIV showed decreased blood glucose and serum insulin and improved insulin sensitivity as well as increased glucose tolerance compared with vehicle injection. Meanwhile, defective hepatic autophagy activity, impaired insulin signaling, increased inflammatory response and mitochondrial dysfunction in liver tissues which are induced by high-fat diet were also effectively alleviated by injection of CaMKIV. Consistent with these results, the addition of CaMKIV to the culture medium of BNL cl.2 hepatocytes markedly restored palmitate-induced hepatic insulin resistance and autophagic imbalance. These effects were nullified by blockade of cyclic AMP response element-binding protein (CREB), indicating the causative role of CREB in action of CaMKIV. Our findings suggested that CaMKIV restores hepatic autophagic imbalance and improves impaired insulin sensitivity via phosphorylated CREB signaling pathway, which may offer novel opportunities for treatment of obesity and diabetes.

scholarly journals Hepatic Insulin Resistance Is Not Pathway Selective in Humans With Nonalcoholic Fatty Liver Disease

2020 ◽  
Author(s):  
Kasper W. ter Horst ◽  
Daniel F. Vatner ◽  
Dongyan Zhang ◽  
Gary W. Cline ◽  
Mariette T. Ackermans ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Bariatric Surgery ◽  
Liver Disease ◽  
Fatty Liver ◽  
Insulin Signaling ◽  
Fatty Liver Disease ◽  
De Novo ◽  
Glucose Production ◽  
Hepatic Insulin Resistance ◽  
Alcoholic Fatty Liver

<b>Objective</b>: Both glucose and triglyceride production are increased in Type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). For decades, the leading hypothesis to explain these paradoxical observations has been selective hepatic insulin resistance, wherein insulin drives <i>de novo</i> lipogenesis (DNL), while failing to suppress glucose production. Here, we aimed to test this hypothesis in humans. <p><b>Research Design and Methods</b>: We recruited obese subjects who met criteria for bariatric surgery with (n=16) or without (n=15) NAFLD and assessed: i) insulin-mediated regulation of hepatic and peripheral glucose metabolism using hyperinsulinemic-euglycemic clamps with [6,6-<sup>2</sup>H<sub>2</sub>]glucose, ii) fasting and carbohydrate-driven hepatic DNL using deuterated water (<sup>2</sup>H<sub>2</sub>O), and iii) hepatocellular insulin signaling in liver biopsies collected during bariatric surgery.</p> <p><b>Results</b>: As compared with subjects without NAFLD, subjects with NAFLD demonstrated impaired insulin-mediated suppression of glucose production and attenuated -not increased- glucose-stimulated/high-insulin lipogenesis. Fructose-stimulated/low-insulin lipogenesis was intact. Hepatocellular insulin signaling, assessed for the first time in humans, exhibited a proximal block in insulin-resistant subjects: signaling was attenuated from the level of the insulin receptor through both glucose <i>and</i> lipogenesis pathways. The carbohydrate-regulated lipogenic transcription factor <i>ChREBP</i> was increased in subjects with NAFLD. </p> <b>Conclusions</b>: Acute increases in lipogenesis in humans with NAFLD are not explained by altered molecular regulation of lipogenesis through a paradoxical increase in lipogenic insulin action; rather, increases in lipogenic substrate availability may be the key. <a></a>

scholarly journals Duration of rise in free fatty acids determines salicylate's effect on hepatic insulin sensitivity

2013 ◽  
Vol 217 (1) ◽  
pp. 31-43 ◽  
Author(s):  
Sandra Pereira ◽  
Wen Qin Yu ◽  
María E Frigolet ◽  
Jacqueline L Beaudry ◽  
Yaniv Shpilberg ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Muscle Protein ◽  
Hepatic Insulin Resistance ◽  
Skeletal Muscle Protein ◽  
Protein Levels ◽  
Peripheral Insulin Resistance ◽  
Plasma Ffa ◽  
A Site

We have shown in rats that sodium salicylate (SS), which inhibits IkBa kinase B (IKKB), prevents hepatic and peripheral insulin resistance caused by short-term (7 h) i.v. administration of Intralipid and heparin (IH). We wished to further determine whether this beneficial effect of SS persisted after prolonged (48 h) IH infusion, which better mimics the chronic free fatty acid (FFA) elevation of obesity. Hence, we performed hyperinsulinemic euglycemic clamps with tritiated glucose methodology to determine hepatic and peripheral insulin sensitivity in rats infused with saline, IH, IH and SS, or SS alone. SS prevented peripheral insulin resistance (P<0.05) caused by prolonged plasma FFA elevation; however, it did not prevent hepatic insulin resistance. In skeletal muscle, protein levels of phospho-IkBa were augmented by prolonged IH administration and this was prevented by SS, suggesting that IH activates while SS prevents the activation of IKKB. Markers of IKKB activation, namely protein levels of phospho-IkBa and IkBa, indicated that IKKB is not activated in the liver after prolonged FFA elevation. Phosphorylation of serine 307 at insulin receptor substrate (IRS)-1, which is a marker of proximal insulin resistance, was not altered by IH administration in the liver, suggesting that this is not a site of hepatic insulin resistance in the prolonged lipid infusion model. Our results suggest that the role of IKKB in fat-induced insulin resistance is time and tissue dependent and that hepatic insulin resistance induced by prolonged lipid elevation is not due to an IRS-1 serine 307 kinase.

Insulin secretion and action and the response of endogenous glucose production to a lack of glucagon suppression in non-diabetic subjects

2021 ◽  
Author(s):  
Jon D Adams ◽  
Aoife M Egan ◽  
Marcello C Laurenti ◽  
Daniel J Schembri Wismayer ◽  
Kent R Bailey ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Action ◽  
Insulin Dose ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Oral Glucose ◽  
Prandial Insulin ◽  
Anthropometric Characteristics ◽  
Glucagon Suppression ◽  
Endogenous Glucose

Type 2 diabetes is a disease characterized by impaired insulin secretion and defective glucagon suppression in the postprandial period. We examined the effect of impaired glucagon suppression on glucose concentrations and Endogenous Glucose Production (EGP) at different degrees of insulin secretory impairment. The contribution of anthropometric characteristics, peripheral, and hepatic insulin action to this variability was also examined. To do so, we studied 54 non-diabetic subjects on two occasions in which endogenous hormone secretion was inhibited by somatostatin, with glucagon infused at a rate of 0.65 ng/kg/min, at 0 min to prevent a fall in glucagon (non-suppressed day) or at 120 min to create a transient fall in glucagon (suppressed day). Subjects received glucose (labeled with [3-3H]-glucose) infused to mimic the systemic appearance of 50g oral glucose. Insulin was infused to mimic a prandial insulin response in 18 subjects, another 18 received 80% of the dose and the remaining 18 received 60%. EGP was measured using the tracer-dilution technique. Decreased prandial insulin resulted in greater % increase in peak glucose but not in integrated glucose concentrations attributable to non-suppressed glucagon. The % change in integrated EGP was unaffected by insulin dose. Multivariate regression analysis, adjusted for age, sex, weight and insulin dose, did not show a relationship between the EGP response to impaired suppression of glucagon and insulin action as measured at the time of screening by oral glucose tolerance. A similar analysis for hepatic insulin action also did not show a relationship with the EGP response. These data indicate that the effect of impaired glucagon suppression on EGP is independent of anthropometric characteristics and insulin action.

scholarly journals Short-term K+ deprivation provokes insulin resistance of cellular K+ uptake revealed with the K+ clamp

2001 ◽  
Vol 280 (1) ◽  
pp. F95-F102 ◽  
Author(s):  
Cheol S. Choi ◽  
Curtis B. Thompson ◽  
Patrick K. K. Leong ◽  
Alicia A. McDonough ◽  
Jang H. Youn
Keyword(s):  
Insulin Resistance ◽  
Atpase Activity ◽  
Infusion Rate ◽  
Insulin Action ◽  
Insulin Dose ◽  
Short Term ◽  
Conscious Rat ◽  
Physiological Concentration ◽  
Glucose Clearance

We aimed to test the feasibility of quantifying insulin action on cellular K+ uptake in vivo in the conscious rat by measuring the exogenous K+ infusion rate needed to maintain constant plasma K+ concentration ([K+]) during insulin infusion. In this “K+ clamp” the K+ infusion rate required to clamp plasma [K+] is a measure of insulin action to increase net plasma K+ disappearance. K+ infusion rate required to clamp plasma [K+] was insulin dose dependent. Renal K+ excretion was not significantly affected by insulin at a physiological concentration (∼90 μU/ml, P > 0.05), indicating that most of insulin-mediated plasma K+ disappearance was due to K+ uptake by extrarenal tissues. In rats deprived of K+ for 2 days, plasma [K+] fell from 4.2 to 3.8 mM, insulin-mediated plasma glucose clearance was normal, but insulin-mediated plasma K+ disappearance decreased to 20% of control, even though there was no change in muscle Na-K-ATPase activity or expression, which is believed to be the main K+ uptake route. After 10 days K+ deprivation, plasma [K+] fell to 2.9 mM, insulin-mediated K+ disappearance decreased to 6% of control (glucose clearance normal), and there were 50% decreases in Na-K-ATPase activity and α2-subunit levels. In conclusion, the present study proves the feasibility of the K+ clamp technique and demonstrates that short-term K+ deprivation leads to a near complete insulin resistance of cellular K+uptake that precedes changes in muscle sodium pump expression.

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