TXNIP Regulates Peripheral Glucose Metabolism in Humans

BACKGROUND: Type 2 diabetes mellitus (T2DM) is characterized by defects in insulin secretion and action. Impaired glucose uptake in skeletal muscle is believed to be one of the earliest features in the natural history of T2DM, although underlying mechanisms remain obscure. METHODS AND FINDINGS: We combined human insulin/glucose clamp physiological studies with genome-wide expression profiling to identify thioredoxin interacting protein (TXNIP) as a gene whose expression is powerfully suppressed by insulin yet stimulated by glucose. In healthy individuals, its expression was inversely correlated to total body measures of glucose uptake. Forced expression of TXNIP in cultured adipocytes significantly reduced glucose uptake, while silencing with RNA interference in adipocytes and in skeletal muscle enhanced glucose uptake, confirming that the gene product is also a regulator of glucose uptake. TXNIP expression is consistently elevated in the muscle of prediabetics and diabetics, although in a panel of 4,450 Scandinavian individuals, we found no evidence for association between common genetic variation in the TXNIP gene and T2DM. CONCLUSIONS: TXNIP regulates both insulin-dependent and insulin-independent pathways of glucose uptake in human skeletal muscle. Combined with recent studies that have implicated TXNIP in pancreatic β-cell glucose toxicity, our data suggest that TXNIP might play a key role in defective glucose homeostasis preceding overt T2DM

Genetic and Nongenetic Regulation of CAPN10 mRNA Expression in Skeletal Muscle.

The gene encoding calpain-10 (CAPN10) has been identified as a candidate gene for type 2 diabetes. Our aim was to study the impact of genetic (heritability and polymorphisms) and nongenetic (insulin, free fatty acids, and age) factors on CAPN10 mRNA expression in skeletal muscle using two different study designs. Muscle biopsies were obtained before and after hyperinsulinemic-euglycemic clamps from 166 young and elderly monozygotic and dizygotic twins as well as from 15 subjects with normal (NGT) or impaired glucose tolerance (IGT) exposed to an Intralipid infusion. We found hereditary effects on both basal and insulin-exposed CAPN10 mRNA expression. Carriers of the type 2 diabetes–associated single nucleotide polymorphism (SNP)-43 G/G genotype had reduced CAPN10 mRNA levels compared with subjects carrying the SNP-43 A-allele. Age had no significant influence on CAPN10 mRNA levels. Insulin had no significant effect on CAPN10 mRNA levels, neither in the twins nor in the basal state of the Intralipid study. However, after a 24-h infusion of Intralipid, we noted a significant increase in CAPN10 mRNA in response to insulin in subjects with NGT but not in subjects with IGT. In conclusion, we provide evidence that mRNA expression of CAPN10 in skeletal muscle is under genetic control. Glucose-tolerant but not glucose-intolerant individuals upregulate their CAPN10 mRNA levels in response to prolonged exposure to fat

Tungtransport i Groruddalen : rapport fra en tverretatlig faggruppe, april 2009

Helhetlig utviklingsplan for Groruddalen (HUG) ble behandlet i bystyret i juni 2006. Målet med planen var å legge strategiske føringer for utviklingen mot et bedre miljø i Groruddalen fram mot 2030. Ved behandlingen av HUG ba bystyret om få utarbeidet et forslag til et tungtransportnett. Et utredningsarbeid ble startet opp i 2007, som et samarbeidsprosjekt mellom Oslo kommune og Statens vegvesen. Rapporten oppsummerer arbeidet. Det foreslås en tiltakspakke som kan gjennomføres på kort og mellomlang sikt. Tiltakene skal bidra til å etablere et tydeligere vegnett for de lengste bilene og samtidig skjerme boligveger som er belastet med tung gjennomfart. Ytterligere tiltak foreslås, tiltak som vil kreve noe mer tid til utredning og planprosess. Forslaget må sees som et skritt i retning av ”visjonen”, som er et attraktivt hovedvegnett med den nye R4-Fossumdiagonalen på plass