Role of hepatic glucose production and glucose uptake in the pathogenesis of fasting hyperglycemia in type 2 diabetes: normalization of glucose kinetics by short-term fasting

1994 ◽  
Vol 78 (3) ◽  
pp. 536-542 ◽  
Author(s):  
F. Fery
Keyword(s):  
Type 2 Diabetes ◽  
Glucose Uptake ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Glucose Kinetics ◽  
Short Term ◽  
Hepatic Glucose

scholarly journals Current understanding of metformin effect on the control of hyperglycemia in diabetes

2016 ◽  
Vol 228 (3) ◽  
pp. R97-R106 ◽  
Author(s):  
Hongying An ◽  
Ling He
Keyword(s):  
Type 2 Diabetes ◽  
Mechanism Of Action ◽  
Insulin Signaling ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Ampk Activation ◽  
First Line ◽  
Hepatic Glucose

Metformin is a first-line oral anti-diabetic agent that has been used clinically to treat patients with type 2 diabetes for over 60 years. Due to its efficacy in therapy and affordable price, metformin is taken by more than 150 million people each year. Metformin improves hyperglycemia mainly through the suppression of hepatic gluconeogenesis along with the improvement of insulin signaling. However, its mechanism of action remains partially understood and controversial, especially in regard to the role of AMPK in metformin's action and the mechanism of AMPK activation. In this review, we discuss recent advances in the understanding of metformin's suppression of hepatic glucose production and the mechanism related to the improvement of insulin signaling.

scholarly journals Effects of 7 days of exercise training on insulin sensitivity and responsiveness in type 2 diabetes mellitus

2009 ◽  
Vol 297 (1) ◽  
pp. E151-E156 ◽  
Author(s):  
John P. Kirwan ◽  
Thomas P. J. Solomon ◽  
Daniel M. Wojta ◽  
Myrlene A. Staten ◽  
John O. Holloszy
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Exercise Training ◽  
Insulin Action ◽  
Insulin Infusion ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Short Term ◽  
Hepatic Glucose

The objectives of this study were to determine whether 1) the improvement in insulin action induced by short-term exercise training in patients with type 2 diabetes is due to an improvement in insulin sensitivity, an improvement in insulin responsiveness, or a combination of improved insulin sensitivity and responsiveness and 2) short-term exercise training results in improved suppression of hepatic glucose production by insulin. Fourteen obese patients with type 2 diabetes, age 64 ± 2 yr, underwent a two-stage hyperinsulinemic euglycemic clamp procedure, first stage 40 mU·m−2·min−1 insulin infusion, second stage 1,000 mU·m−2·min−1 insulin infusion, together with a [3-3H]glucose infusion, before and after 7 days of exercise. The training consisted of 30 min of cycling and 30 min of treadmill walking at ∼70% of maximal aerobic capacity daily for 7 days. The exercise program resulted in improvements in insulin action in the absence of weight loss. Glucose disposal rates during the euglycemic clamp were significantly increased at both hyperinsulinemic stages after training (40 mU: 1.84 ± 0.32 to 2.67 ± 0.37 mg·kg−1·min−1, P < 0.0001; 1,000 mU: 7.57 ± 0.61 to 8.84 ± 0.56 mg·kg−1·min−1, P = 0.008). Hepatic glucose production, both in the basal state (3.17 ± 0.43 vs. 2.54 ± 0.26 mg·kg−1·min−1, P = 0.05) and during the 40-mU clamp stage (1.15 ± 0.41 vs. 0.46 ± 0.20 mg·kg−1·min−1, P = 0.03), was significantly reduced after training. One week of vigorous exercise training can induce significant improvements in insulin action in type 2 diabetes. These improvements include increased peripheral insulin sensitivity and responsiveness as well as enhanced suppression of hepatic glucose production.

scholarly journals Novel liver-specific TORC2 siRNA corrects hyperglycemia in rodent models of type 2 diabetes

2009 ◽  
Vol 297 (5) ◽  
pp. E1137-E1146 ◽  
Author(s):  
Maziyar Saberi ◽  
David Bjelica ◽  
Simon Schenk ◽  
Takeshi Imamura ◽  
Gautam Bandyopadhyay ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Primary Mouse Hepatocytes ◽  
Primary Mouse ◽  
Hepatic Glucose ◽  
Zdf Rats ◽  
Mouse Hepatocytes

The transcription factor TORC2 [transducer of regulated cAMP-responsive element-binding protein (CREB) activity 2] is a major regulator of hepatic gluconeogenesis and is increased in hyperglycemic rodent models. Because chronic hyperglycemia and increased hepatic glucose production, via increased gluconeogenesis, is a key feature of type 2 diabetes, an effective in vivo method to efficiently knock down TORC2 could provide a potential therapy for treating hyperglycemia and type 2 diabetes. To assess this, primary mouse hepatocytes, high-fat diet (HFD)-fed mice, and Zucker diabetic fatty (ZDF) rats were treated with a siRNA against TORC2 (siTORC2), which was delivered via a novel lipid nanoparticle system, or control siRNA (siCON). Compared with siCON, administration of siTORC2 resulted in highly efficient, sustained (1–3 wk) knockdown of TORC2 and its gluconeogenic target genes phospho enolpyruvate carboxykinase and glucose-6-phophatase in primary mouse hepatocytes and in the livers of HFD-fed mice. In mice, this knockdown was specific to the liver and did not occur in kidney, skeletal muscle, or adipose tissue. In HFD-fed mice, siTORC2 reduced in vivo gluconeogenic capacity, fasting hepatic glucose production, and hyperglycemia, and led to improved hepatic and skeletal muscle insulin sensitivity. siTORC2 treatment also improved systemic hyperglycemia in ZDF rats. In conclusion, these results demonstrate the importance of TORC2 in modulating HGP in vivo and highlight a novel, liver-specific siRNA approach for the potential treatment of hyperglycemia and type 2 diabetes.

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.

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