Hepatic glucose production and insulin sensitivity and responsiveness in iron-deficient anemic rats

1993 ◽  
Vol 264 (3) ◽  
pp. E380-E390 ◽  
Author(s):  
M. J. Borel ◽  
J. L. Beard ◽  
P. A. Farrell
Keyword(s):  
Insulin Sensitivity ◽  
Hepatic Glucose Production ◽  
Insulin Dose ◽  
Glucose Production ◽  
Deficiency Anemia ◽  
Response Curves ◽  
Iron Deficient ◽  
Hepatic Glucose ◽  
Basal Plasma ◽  
Insulin Responsiveness

We performed euglycemic hyperinsulinemic glucose clamps at insulin infusion rates of 1.9, 4.0, 9.3, and 19.3 mU.kg-1 x min-1 in rats with varying severities of iron deficiency anemia (IDA; mean hemoglobin concentrations of 59, 79, 107, and 137 g/l) to assess the effect of IDA on insulin sensitivity and responsiveness. Glucose appearance and disappearance (Rd) rates were determined using a primed continuous infusion of [3-3H]glucose. Basal plasma glucose and insulin concentrations were similar between the IDA and control rats. Basal hepatic glucose production was significantly (P = 0.0001) elevated in the two most anemic groups (13.6 +/- 2.4 and 12.6 +/- 3.1 vs. 10.6 +/- 2.2 and 10.2 +/- 2.0 mg.kg-1 x min-1). A significant upward shift in the insulin dose-response curves for Rd indicated an increase in peripheral insulin responsiveness in the two most anemic groups while a slight leftward shift was suggestive of an increase in insulin sensitivity in all three anemic groups. Hepatic insulin sensitivity and responsiveness were unaffected by IDA. We conclude that increased glucose utilization rates in IDA rats are due primarily to an increase in peripheral insulin responsiveness.

Effects of acute running exercise on whole body insulin action in obese male SHHF/Mcc-facp rats

1994 ◽  
Vol 77 (2) ◽  
pp. 534-541 ◽  
Author(s):  
J. Gao ◽  
W. M. Sherman ◽  
S. A. McCune ◽  
K. Osei
Keyword(s):  
Heart Failure ◽  
Insulin Sensitivity ◽  
Acute Exercise ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Whole Body ◽  
Glucose Disposal ◽  
Hepatic Glucose ◽  
Insulin Responsiveness ◽  
Obese Male

This study utilized the obese male spontaneously hypertensive heart failure rat (SHHF/Mcc-facp), which has metabolic features very similar to human non-insulin-dependent diabetes mellitus. The purpose of this study was to assess the insulin sensitivity and responsiveness of whole body glucose disposal and insulin suppressability of hepatic glucose production with use of the euglycemic-hyperinsulinemic clamp procedure in 12- to 15-wk-old SHHF/Mcc-facp rats at rest (OS) and 2.5 h after a single session of acute exercise (OE). Lean male SHHF/Mcc-facp rats were sedentary (LS) control animals. At least three clamps producing different insulin-stimulated responses were performed on each animal in a randomized order. At this age the obese animals are normotensive and have not developed congestive heart failure. Compared with LS, OS were significantly hyperglycemic and hyperinsulinemic and insulin sensitivity and responsiveness of whole body glucose uptake and insulin suppressability of hepatic glucose production were significantly decreased. Compared with LS and OS, acute exercise significantly decreased resting plasma glucose but did not alter plasma insulin. Compared with OS, acute exercise significantly increased the insulin responsiveness of whole body glucose disposal but did not affect the sensitivity of whole body glucose disposal or insulin suppressability of hepatic glucose production. Compared with LS, however, acute exercise did not “normalize” the insulin responsiveness of whole body glucose disposal. Thus a single acute exercise session improves but does not normalize whole body insulin resistance in the SHHF/Mcc-facp rat.

scholarly journals Differential impact of selective GH deficiency and endogenous GH excess on insulin-mediated actions in muscle and liver of male mice

2014 ◽  
Vol 307 (10) ◽  
pp. E928-E934 ◽  
Author(s):  
Jose Cordoba-Chacon ◽  
Manuel D. Gahete ◽  
Owen P. McGuinness ◽  
Rhonda D. Kineman
Keyword(s):  
Insulin Sensitivity ◽  
Gh Deficiency ◽  
Hepatic Glucose Production ◽  
Insulin Receptors ◽  
Glucose Production ◽  
Reciprocal Relationship ◽  
Hepatic Insulin Resistance ◽  
Hepatic Lipid Metabolism ◽  
Hepatic Glucose ◽  
Gh Excess

A reciprocal relationship between insulin sensitivity and glucose tolerance has been reported in some mouse models and humans with isolated changes in growth hormone (GH) production and signaling. To determine if this could be explained in part by tissue-specific changes in insulin sensitivity, hyperinsulinemic-euglycemic clamps were performed in mice with adult-onset, isolated GH deficiency and in mice with elevated endogenous GH levels due to somatotrope-specific loss of IGF-I and insulin receptors. Our results demonstrate that circulating GH levels are negatively correlated with insulin-mediated glucose uptake in muscle but positively correlated with insulin-mediated suppression of hepatic glucose production. A positive relationship was also observed between GH levels and endpoints of hepatic lipid metabolism known to be regulated by insulin. These results suggest hepatic insulin resistance could represent an early metabolic defect in GH deficiency.

scholarly journals Phenotypic and Molecular Evaluation of a Chromosome 1q Region with Linkage and Association to Type 2 Diabetes in Humans

2009 ◽  
Vol 94 (4) ◽  
pp. 1401-1408 ◽  
Author(s):  
Hua Wang ◽  
Nicholas P. Hays ◽  
Swapan K. Das ◽  
Rebekah L. Craig ◽  
Winston S. Chu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Hepatic Glucose Production ◽  
Linkage Disequilibrium Block ◽  
Glucose Production ◽  
Risk Haplotype ◽  
Expression Of Genes ◽  
Hepatic Glucose

Abstract Objective: Linkage to type 2 diabetes (T2D) is well replicated on chromosome 1q21-q23. Within this region, T2D was associated with common single nucleotide polymorphisms that marked an extended linkage disequilibrium block, including the liver pyruvate kinase gene (PKLR), in several European-derived populations. In this study we sought to determine the molecular basis for the association and the phenotypic consequences of the risk haplotype. Research Design and Methods: Genes surrounding PKLR were resequenced in European-American and African-American cases and controls, and association with T2D was tested. Copy number variants (CNVs) were tested for four regions with real-time PCR. Expression of genes in the region was tested in adipose and muscle from nondiabetic subjects with each genotype. Insulin secretion, insulin sensitivity, and hepatic glucose production were tested in nondiabetic individuals with each haplotype combination. Results: No coding variant in the region was associated with T2D. CNVs were rare and not associated with T2D. PKLR was not expressed in available tissues, but expression of genes HCN3, CLK2, SCAMP3, and FDPS was not associated with haplotype combinations in adipose or muscle. Haplotype combinations were not associated with insulin secretion or peripheral insulin sensitivity, but homozygous carriers of the risk haplotype had increased hepatic glucose production during hyperinsulinemia. Conclusions: Noncoding variants in the PKLR region likely alter gene expression of one or more genes. Our extensive physiological and molecular studies suggest increased hepatic glucose production and reduced hepatic insulin sensitivity, thus pointing to PKLR itself as the most likely candidate gene in this population.

scholarly journals Systemic bile acids induce insulin resistance in a TGR5-independent manner

2019 ◽  
Vol 316 (5) ◽  
pp. E782-E793 ◽  
Author(s):  
Kristen E. Syring ◽  
Travis J. Cyphert ◽  
Thomas C. Beck ◽  
Charles R. Flynn ◽  
Nicholas A. Mignemi ◽  
...  
Keyword(s):  
Bile Acid ◽  
Insulin Sensitivity ◽  
Bile Acids ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Farnesoid X Receptor ◽  
Serum Bile Acid ◽  
Hepatic Insulin Sensitivity ◽  
Hepatic Glucose ◽  
The Impact

Bile acids are involved in the emulsification and absorption of dietary fats, as well as acting as signaling molecules. Recently, bile acid signaling through farnesoid X receptor and G protein-coupled bile acid receptor (TGR5) has been reported to elicit changes in not only bile acid synthesis but also metabolic processes, including the alteration of gluconeogenic gene expression and energy expenditure. A role for bile acids in glucose metabolism is also supported by a correlation between changes in the metabolic state of patients (i.e., obesity or postbariatric surgery) and altered serum bile acid levels. However, despite evidence for a role for bile acids during metabolically challenging settings, the direct effect of elevated bile acids on insulin action in the absence of metabolic disease has yet to be investigated. The present study examines the impact of acutely elevated plasma bile acid levels on insulin sensitivity using hyperinsulinemic-euglycemic clamps. In wild-type mice, elevated bile acids impair hepatic insulin sensitivity by blunting the insulin suppression of hepatic glucose production. The impaired hepatic insulin sensitivity could not be attributed to TGR5 signaling, as TGR5 knockout mice exhibited a similar inhibition of insulin suppression of hepatic glucose production. Canonical insulin signaling pathways, such as hepatic PKB (or Akt) activation, were not perturbed in these animals. Interestingly, bile acid infusion directly into the portal vein did not result in an impairment in hepatic insulin sensitivity. Overall, the data indicate that acute increases in circulating bile acids in lean mice impair hepatic insulin sensitivity via an indirect mechanism.

Estrogen Improves Insulin Sensitivity and Suppresses Hepatic Glucose Production via the Transcription Factor Foxo1

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 1875-P ◽  
Author(s):  
HUI YAN ◽  
FENGHUA ZHOU ◽  
WANBAO YANG ◽  
QUAN PAN ◽  
ZHENG SHEN ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Insulin Sensitivity ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hepatic Glucose

scholarly journals The Pattern of Growth Hormone Delivery to Peripheral Tissues Determines Insulin-Like Growth Factor-1 and Lipolytic Responses in Obese Subjects

2009 ◽  
Vol 94 (8) ◽  
pp. 2828-2834 ◽  
Author(s):  
Sowmya Surya ◽  
Jeffrey F. Horowitz ◽  
Naila Goldenberg ◽  
Alla Sakharova ◽  
Matthew Harber ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Medical Center ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Oral Glucose ◽  
Peripheral Tissues ◽  
Tracer Techniques ◽  
Hepatic Glucose ◽  
Igf I ◽  
Obese Subjects

Context: It is unclear whether the pattern of GH delivery to peripheral tissues has important effects. Objective: The aim of the study was to compare the effects of pulsatile vs. continuous administration of GH upon metabolic and IGF-I parameters in obese subjects. Setting: The study was conducted at the General Clinical Research Center at the University of Michigan Medical Center. Participants: Four men and five women with abdominal obesity (body mass index, 33 ± 3 kg/m2; body fat, 40 ± 3%) participated in the study. Intervention: GH (0.5 mg/m2 · d) was given iv for 3 d as: 1) continuous infusion (C); and 2) pulsatile boluses (P) (15% of the dose at 0700, 1300, and 1800 h and 55% at 2400 h). These trials were preceded by a basal period (B) when subjects received normal saline. Main Outcome Measures: Rate of lipolysis and hepatic glucose production were evaluated using stable isotope tracer techniques. The composite index of insulin sensitivity (Matsuda index) was assessed using oral glucose tolerance test. Results: The increase in plasma IGF-I concentrations was greater (P < 0.05) with continuous GH infusion (211 ± 31, 423 ± 38, and 309 ± 34 μg/liter for B, C, and P, respectively). Muscle IGF-I mRNA was significantly increased (P < 0.05) only after the continuous GH infusion (1.2 ± 0.4, 4.4 ± 1.3, and 2.3 ± 0.6 arbitrary units, for B, C, and P, respectively). Only pulsatile GH augmented the rate of lipolysis (4.1 ± 0.3, 4.8 ± 0.7, and 7.1 ± 1.1 μmol/kg · min for B, C, and P, respectively). GH had no effect on hepatic glucose production, but both modes of GH administration were equally effective in impairing insulin sensitivity. Conclusion: These findings indicate that, in obese subjects, discrete components of GH secretory pattern may differentially affect IGF-I generation and lipolytic responses.

scholarly journals Knockdown of Neuropeptide Y in the Dorsomedial Hypothalamus Promotes Hepatic Insulin Sensitivity in Male Rats

Endocrinology ◽  
2016 ◽  
Vol 157 (12) ◽  
pp. 4842-4852 ◽  
Author(s):  
Lin Li ◽  
C. Barbier de La Serre ◽  
Ni Zhang ◽  
Liang Yang ◽  
Hong Li ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Neuropeptide Y ◽  
Glucose Homeostasis ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Inhibitory Effect ◽  
Male Rats ◽  
Motor Nucleus ◽  
Hepatic Insulin Sensitivity ◽  
Hepatic Glucose

Recent evidence has shown that alterations in dorsomedial hypothalamic (DMH) neuropeptide Y (NPY) signaling influence glucose homeostasis, but the mechanism through which DMH NPY acts to affect glucose homeostasis remains unclear. Here we report that DMH NPY descending signals to the dorsal motor nucleus of the vagus (DMV) modulate hepatic insulin sensitivity to control hepatic glucose production in rats. Using the hyperinsulinemic-euglycemic clamp, we revealed that knockdown of NPY in the DMH by adeno-associated virus-mediated NPY-specific RNAi promoted insulin’s action on suppression of hepatic glucose production. This knockdown silenced DMH NPY descending signals to the DMV, leading to an elevation of hepatic vagal innervation. Hepatic vagotomy abolished the inhibitory effect of DMH NPY knockdown on hepatic glucose production, but this glycemic effect was not affected by vagal deafferentation. Together, these results demonstrate a distinct role for DMH NPY in the regulation of glucose homeostasis through the hepatic vagal efferents and insulin action on hepatic glucose production.

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.

In vivo metabolic changes as studied longitudinally after ventromedial hypothalamic lesions

1986 ◽  
Vol 250 (6) ◽  
pp. E662-E668 ◽  
Author(s):  
L. Penicaud ◽  
F. Rohner-Jeanrenaud ◽  
B. Jeanrenaud
Keyword(s):  
Glucose Metabolism ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Tissue Response ◽  
Insulin Concentration ◽  
Insulin Resistant ◽  
Hepatic Glucose ◽  
Insulin Responsiveness ◽  
Total Glucose

Ventromedial hypothalamic (VMH)-lesioned rats were tested 1 and 6 wk after the lesions to determine, by euglycemic-hyperinsulinemic clamps, their tissue response to insulin. One week after the lesions, total glucose metabolism was more sensitive and responsive to insulin than in age-matched controls. In the two groups, hepatic glucose production was suppressed at almost identical insulin concentrations (approximately 550 microU/ml). Six weeks after the VMH lesions, the increased insulin responsiveness of total glucose metabolism disappeared and glucose metabolism became less insulin sensitive (right, shifted dose-response curve) than that of control animals. Furthermore, hepatic glucose production of VMH-lesioned rats was now inhibited by 45% at most and at the supraphysiological insulin concentration of 16,000 microU/ml, while it was totally suppressed by 550 microU/ml of the hormone in age-matched controls. This defect was accompanied by a lack of decrease in plasma glucagon levels during the clamps carried out at maximal insulin concentration. In summary, in a first phase after VMH lesion, rats are hypersensitive and hyperresponsive to insulin; and in a later phase, when obesity is well established, VMH-lesioned rats become insulin resistant and are characterized by a decreased in vivo sensitivity and responsiveness of liver and muscles to the hormone.

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