Elevated Plasma Levels of 3-Hydroxyisobutyric Acid Are Associated With Incident Type 2 Diabetes

Branched-chain amino acids (BCAAs) metabolite, 3-Hydroxyisobutyric acid (3-HIB) has been identified as a secreted mediator of endothelial cell fatty acid transport and insulin resistance (IR) using animal models. To identify if 3-HIB is a marker of human IR and future risk of developing Type 2 diabetes (T2D), we measured plasma levels of 3-HIB and associated metabolites in around 10,000 extensively phenotyped individuals. The levels of 3-HIB were increased in obesity but not robustly associated with degree of IR after adjusting for BMI. Nevertheless, also after adjusting for obesity and plasma BCAA, 3-HIB levels were associated with future risk of incident T2D. We also examined the effect of 3-HIB on fatty acid uptake in human cells and found that both HUVEC and human cardiac endothelial cells respond to 3-HIB whereas human adipose tissue-derived endothelial cells do not respond to 3-HIB. In conclusion, we found that increased plasma level of 3-HIB is a marker of future risk of T2D and 3-HIB may be important for the regulation of metabolic flexibility in heart and muscles

Type 2 Diabetes, Independent of Obesity and Age, is Characterized by Senescent and Dysfunctional Mature Human Adipose Cells

Obesity with dysfunctional adipose cells is the major cause of the current epidemic of T2D. We examined senescence in human adipose tissue cells from age- and BMI-matched lean, obese and obese T2D individuals and found mature and fully differentiated adipose cells from obese and, more pronounced, from T2D individuals to exhibit increased senescence similar to what we previously have shown in the progenitor cells. Degree of adipose cell senescence was positively correlated with whole-body insulin resistance and adipose cell size. Adipose cell protein analysis revealed dysfunctional cells in T2D with increased senescence markers, reduced PPARγ, GLUT4 and pS473AKT. Consistent with a recent study, we found the cell cycle regulator cyclin D1 to be increased in obese cells but also further elevated in T2D cells, closely correlating with senescence markers, ambient donor glucose and, more inconsistently, with plasma insulin levels. Furthermore, fully differentiated adipose cells were susceptible to experimentally induced senescence, to conditioned medium increasing cyclin D1 and also responsive to senolytic agents. Thus, fully mature human adipose cells from obese and, more pronounced, T2D subjects become senescent and SASP secretion by senescent progenitor cells can play an important role in addition to donor hyperinsulinemia

Regulation of metabolism and inflammation in liver and skeletal muscle

Type 2 diabetes (T2D) is a complex metabolic disorder characterised by hyperinsulinaemia, hyperglycaemia and dyslipidaemia. Obesity is the major risk factor for development of insulin resistance, a main predictor of T2D. Recent evidence indicates that nutrient excess and obesity lead to chronic low-grade inflammation in metabolic tissues, which further promotes insulin resistance. AMP-activated protein kinase (AMPK), a central regulator of energy homeostasis, increases insulin sensitivity in liver and skeletal muscle and lowers the plasma glucose level, thus reverting the major metabolic disturbances in T2D. Serine/threonine protein kinase 25 (STK25) was found to be differentially expressed in skeletal muscle, comparing AMPKγ3 (Prkag3-/-) knockout mice to wild-type littermates, indicating a potential role for STK25 in regulation of energy homeostasis in skeletal muscle. In Paper I, genes regulating the circadian rhythm (Cry2, Nr1d1 and Bhlhb2) were shown to be differentially expressed in skeletal muscle from wild-type mice treated with the AMPK agonist 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), while they remained unaltered in AMPKγ3 knockout mice. Furthermore, the respiratory exchange ratio (RER) was elevated during the dark period of observation in wild-type mice reflecting a diurnal shift in substrate utilisation from lipid oxidation at daytime to carbohydrate utilisation during nighttime. However, no day/night shift in the RER profile was observed in Prkag3-/- littermates. Thus, this study suggests that APMK, as a central energy sensor, could be one important node linking energy metabolism to the circadian clock function. In Papers II and III, the AMPK agonists, AICAR and metformin, are shown to markedly decrease the expression of IL-6-induced serum amyloid A (SAA) cluster genes, haptoglobin and suppressor of cytokine signalling 3 (SOCS3) in the human hepatocyte cell line HepG2. By repressing AMPK activity with small interfering (si)RNA the inhibitory effect of AMPK on SAA expression by both AICAR and metformin was reversed (Paper II), indicating that the effect of the agonists is mediated by AMPK activation. Further, we show that AMPK interferes with IL-6 signalling by decreasing IL-6-induced phosphorylation of Janus kinase 1 (JAK1), src homology 2 domain containing protein tyrosine phosphatase 2 (SHP2) and signal transducer and activator of transcription 3 (STAT3) in HepG2 cells (Papers II and III). In addition, pharmacological activation of AMPK was shown to repress IL-6-induced inflammation in vivo by suppression of STAT3 activity in mouse liver (Paper III). This suggests that AMPK is an important intracellular link between metabolic and inflammatory pathways in liver. In Paper IV we show that partial reduction of STK25 by siRNA increases uncoupling protein 3 (UCP3), glucose transporter 1 (GLUT1), GLUT4 and hexokinase 2 (HK2) in the rodent myoblast cell line L6, both at mRNA and protein level. Correspondingly, the rates of palmitate oxidation and insulin-stimulated glucose uptake were elevated after partial depletion of STK25. In conclusion, our studies suggest a role of STK25 as a negative regulator of glucose and lipid metabolism in skeletal muscle. Impaired glucose uptake and fatty acid metabolism by skeletal muscle is a hallmark of insulin resistance, and therefore, STK25 could be an important new mediator to be evaluated for therapeutic intervention in T2D and related complications

Increased cell senescence in human metabolic disorders

: Cell senescence (CS) is at the nexus between aging and associated chronic disorders, and aging increases the burden of CS in all major metabolic tissues. However, CS is also increased in adult obesity, type 2 diabetes (T2D), and nonalcoholic fatty liver disease independent of aging. Senescent tissues are characterized by dysfunctional cells and increased inflammation, and both progenitor cells and mature, fully differentiated and nonproliferating cells are afflicted. Recent studies have shown that hyperinsulinemia and associated insulin resistance (IR) promote CS in both human adipose and liver cells. Similarly, increased CS promotes cellular IR, showing their interdependence. Furthermore, the increased adipose CS in T2D is independent of age, BMI, and degree of hyperinsulinemia, suggesting premature aging. These results suggest that senomorphic/senolytic therapy may become important for treating these common metabolic disorders

Arthritis suppression by NADPH activation operates through an interferon-β pathway-2

<p><b>Copyright information:</b></p><p>Taken from "Arthritis suppression by NADPH activation operates through an interferon-β pathway"</p><p>http://www.biomedcentral.com/1741-7007/5/19</p><p>BMC Biology 2007;5():19-19.</p><p>Published online 9 May 2007</p><p>PMCID:PMC1884140.</p><p></p>m groups of four animals. Levels of significance were calculated using Student's -test (***< 0.001)

Arthritis suppression by NADPH activation operates through an interferon-β pathway-8

<p><b>Copyright information:</b></p><p>Taken from "Arthritis suppression by NADPH activation operates through an interferon-β pathway"</p><p>http://www.biomedcentral.com/1741-7007/5/19</p><p>BMC Biology 2007;5():19-19.</p><p>Published online 9 May 2007</p><p>PMCID:PMC1884140.</p><p></p>he strains were calculated using Student's -test (*< 0.05)

Arthritis suppression by NADPH activation operates through an interferon-β pathway-5

<p><b>Copyright information:</b></p><p>Taken from "Arthritis suppression by NADPH activation operates through an interferon-β pathway"</p><p>http://www.biomedcentral.com/1741-7007/5/19</p><p>BMC Biology 2007;5():19-19.</p><p>Published online 9 May 2007</p><p>PMCID:PMC1884140.</p><p></p>culated using Student's -test (**< 0.01)

Arthritis suppression by NADPH activation operates through an interferon-β pathway-4

<p><b>Copyright information:</b></p><p>Taken from "Arthritis suppression by NADPH activation operates through an interferon-β pathway"</p><p>http://www.biomedcentral.com/1741-7007/5/19</p><p>BMC Biology 2007;5():19-19.</p><p>Published online 9 May 2007</p><p>PMCID:PMC1884140.</p><p></p>culated using Student's -test (*< 0.05; **< 0.01)