DNA microarrays can be used to identify gene expression changes characteristic of human disease. This is challenging, however, when relevant differences are subtle at the level of individual genes. We introduce an analytical strategy, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes. Using this approach, we identify a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle. Expression of these genes is high at sites of insulin-mediated glucose disposal, activated by PGC-1α and correlated with total-body aerobic capacity. Our results associate this gene set with clinically important variation in human metabolism and illustrate the value of pathway relationships in the analysis of genomic profiling experiments.

/pdf/pgc-1alpha-responsive-genes-involved-in-oxidative-1t3qxw5cbf.pdf

PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes

The metabolic syndrome

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(05)61032-X.pdf

Type 2 diabetes - principles of pathogenesis and therapy

Skeletal muscle is strongly dependent on oxidative phosphorylation for energy production. Because the insulin resistance of skeletal muscle in type 2 diabetes and obesity entails dysregulation of the oxidation of both carbohydrate and lipid fuels, the current study was undertaken to examine the potential contribution of perturbation of mitochondrial function. Vastus lateralis muscle was obtained by percutaneous biopsy during fasting conditions from lean (n = 10) and obese (n = 10) nondiabetic volunteers and from volunteers with type 2 diabetes (n = 10). The activity of rotenone-sensitive NADH:O(2) oxidoreductase, reflecting the overall activity of the respiratory chain, was measured in a mitochondrial fraction by a novel method based on providing access for NADH to intact mitochondria via alamethicin, a channel-forming antibiotic. Creatine kinase and citrate synthase activities were measured as markers of myocyte and mitochondria content, respectively. Activity of rotenone-sensitive NADH:O(2) oxidoreductase was normalized to creatine kinase activity, as was citrate synthase activity. NADH:O(2) oxidoreductase activity was lowest in type 2 diabetic subjects and highest in the lean volunteers (lean 0.95 +/- 0.17, obese 0.76 +/- 0.30, type 2 diabetes 0.56 +/- 0.14 units/mU creatine kinase; P < 0.005). Also, citrate synthase activity was reduced in type 2 diabetic patients (lean 3.10 +/- 0.74, obese 3.24 +/- 0.82, type 2 diabetes 2.48 +/- 0.47 units/mU creatine kinase; P < 0.005). As measured by electron microscopy, skeletal muscle mitochondria were smaller in type 2 diabetic and obese subjects than in muscle from lean volunteers (P < 0.01). We conclude that there is an impaired bioenergetic capacity of skeletal muscle mitochondria in type 2 diabetes, with some impairment also present in obesity.

https://diabetes.diabetesjournals.org/content/diabetes/51/10/2944.full.pdf

Dysfunction of Mitochondria in Human Skeletal Muscle in Type 2 Diabetes

Metabolic control through the PGC-1 family of transcription coactivators.

FoxO1 plays an important role in mediating the effect of insulin on hepatic metabolism Increased FoxO1 activity is associated with reduced ability of insulin to regulate hepatic glucose production However, the underlying mechanism and physiology remain unknown We studied the effect of FoxO1 on the ability of insulin to regulate hepatic metabolism in normal vs insulin-resistant liver under fed and fasting conditions FoxO1 gain of function, as a result of adenovirus-mediated or transgenic expression, augmented hepatic gluconeogenesis, accompanied by decreased glycogen content and increased fat deposition in liver Mice with excessive FoxO1 activity exhibited impaired glucose tolerance Conversely, FoxO1 loss of function, caused by hepatic production of its dominant-negative variant, suppressed hepatic gluconeogenesis, resulting in enhanced glucose disposal and improved insulin sensitivity in db/db mice FoxO1 expression becomes deregulated, culminating in increased nuclear localization and accounting for its increased transcription activity in livers of both high fat-induced obese mice and diabetic db/db mice Increased FoxO1 activity resulted in up-regulation of hepatic peroxisome proliferator-activated receptor-gamma coactivator-1beta, fatty acid synthase, and acetyl CoA carboxylase expression, accounting for increased hepatic fat infiltration These data indicate that hepatic FoxO1 deregulation impairs the ability of insulin to regulate hepatic metabolism, contributing to the development of hepatic steatosis and abnormal metabolism in diabetes

/pdf/aberrant-forkhead-box-o1-function-is-associated-with-7jgc6pxwjs.pdf

Aberrant Forkhead box O1 function is associated with impaired hepatic metabolism.

High-fructose consumption is associated with insulin resistance and diabetic dyslipidemia, but the underlying mechanism is unclear. We show in hamsters that high-fructose feeding stimulated forkhead box O1 (FoxO1) production and promoted its nuclear redistribution in liver, correlating with augmented apolipoprotein C-III (apoC-III) production and impaired triglyceride metabolism. High-fructose feeding upregulated peroxisome proliferator-activated receptor-γ coactivator-1β and sterol regulatory element binding protein-1c expression, accounting for increased fat infiltration in liver. High-fructose-fed hamsters developed hypertriglyceridemia, accompanied by hyperinsulinemia and glucose intolerance. These metabolic aberrations were reversible by fenofibrate, a commonly used anti-hypertriglyceridemia agent that is known to bind and activate peroxisome proliferator-activated receptor-α (PPARα). PPARα physically interacted with, but functionally antagonized, FoxO1 in hepatic apoC-III expression. These data underscore the importance of FoxO1 deregulation in the pathogenesis of hypertriglyceridemia in high-fructose-fed hamsters. Counterregulation of hepatic FoxO1 activity by PPARα constitutes an important mechanism by which fibrates act to curb apoC-III overproduction and ameliorate hypertriglyceridemia.

/pdf/ppara-mediates-the-hypolipidemic-action-of-fibrates-by-1dxqdc4mew.pdf

PPARα mediates the hypolipidemic action of fibrates by antagonizing FoxO1

: Introduction: Pig islets have been proposed as an alternative to human islets for clinical use, but their use is limited by rejection. The availability of genetically modified pigs devoid of α1,3-galactosyltransferase might provide islets more suitable for xenotransplantation. To limit the costs involved in the logistics and health care of pigs for clinical xenotransplantation, we have studied whether younger, rather than older, pigs that are typically preferred can be used as islet donors.



Methods:  We utilized pancreases from Yorkshire and White Landrace wild-type pigs and α1,3-galactosyltransferase gene-knockout pigs of three main different age and size groups: (i) 2 yr of age, inclusive of retired breeders. We compared isolation yield and in vitro and in vivo function of islet cells obtained from these groups.



Results:  Islets from adult pigs (>2 yr) offered not only higher islet yields, but retained the ability to preserve intact morphology during the isolation process and culture, in association with high functional properties after transplantation. Following isolation, islet cells from young (<6 m) and young-adult (6 to 12 m) pigs dissociated into small aggregates and single cells, and exhibited inferior functional properties than adult islets both in vitro and in vivo.



Conclusions:  These data support the conclusion that, in view of the large number of islets needed to maintain normoglycemia after xenotransplantation, organ-source pigs need to reach adult age (>2 yr) before being considered optimal islet donors, in spite of the higher costs involved.

Isolation outcome and functional characteristics of young and adult pig pancreatic islets for transplantation studies.

Human proinsulin C-peptide reduces high glucose-induced proliferation and NF-κB activation in vascular smooth muscle cells

Muscle contains the largest reservoir of glycogen (Glyc), a depot that is closely regulated and with influence on insulin sensitivity. The current study examines muscle Glyc in type 2 diabetes mell...

https://www.physiology.org/doi/pdf/10.1152/ajpendo.00015.2004

Jing He

Papers

Aberrant Forkhead box O1 function is associated with impaired hepatic metabolism.

PPARα mediates the hypolipidemic action of fibrates by antagonizing FoxO1

Isolation outcome and functional characteristics of young and adult pig pancreatic islets for transplantation studies.

Human proinsulin C-peptide reduces high glucose-induced proliferation and NF-κB activation in vascular smooth muscle cells

Muscle Glycogen Content in Type 2 Diabetes Mellitus