Glucose metabolism: key endogenous regulator of ß-cell replication and survival.

Recent studies in mice have shown that pancreatic ß-cells have a significant potential for regeneration, suggesting that regenerative therapy for diabetes is feasible. Genetic lineage tracing studies indicate that ß-cell regeneration is based on the replication of fully differentiated, insulin-positive ß-cells. Thus, a major challenge for this field is to identify and enhance the molecular pathways that control ß-cell replication and mass. We review evidence, from human genetics and mouse models, that glucose is a major signal for ß-cell replication. The mitogenic effect of blood glucose is transmitted via glucose metabolism within ß-cells, and through a signalling cascade that resembles the pathway for glucose-stimulated insulin secretion. We introduce the concept that the individual ß-cell workload, defined as the amount of insulin that an individual ß-cell must secrete to maintain euglycaemia, is the primary determinant of replication, survival and mass. We also propose that a cell-autonomous pathway, similar to that regulating replication, appears to be responsible for at least some of the toxic effects of glucose on ß-cells. Understanding and uncoupling the mitogenic and toxic effects of glucose metabolism on ß-cells may allow for the development of effective regenerative therapies for diabetes.

Macrophage cholesterol metabolism, apolipoprotein E, and scavenger receptor AI/II mRNA in atherosclerosis-susceptible and -resistant mice.

Female mice known to be susceptible (C57BL) and resistant (C3H and BALB/c) to diet-induced atherosclerosis were studied. Feeding of a cholate-containing atherogenic diet for 1 month resulted in an increase in plasma total cholesterol, little or no change in total phospholipids and high density lipoprotein (HDL) cholesterol, and a fall in HDL phospholipid, which was most pronounced in the C57BL strain. In elicited macrophages, cholesterol esterification was lower with acetylated low density lipoprotein (acLDL) and higher with beta-very low density lipoprotein (beta-VLDL) in C57BL than in C3H or BALB/C strains. In resident macrophages, acLDL enhanced cholesterol esterification more than did rabbit beta-VLDL. With acLDL, more apolipoprotein E (apoE) was recovered in all macrophage cultures. In macrophages from chow-fed mice, most apoE was in the medium, whereas in mice fed an atherogenic diet, half of the apoE was in the cells. ApoE protein was highest in macrophages from BALB/c mice fed an atherogenic diet; an increase in apoE mRNA occurred in BALB/c and C3H macrophages. Scavenger receptor AI/II mRNA was significantly higher in macrophages from atherosclerosis-resistant mice. Thus, higher HDL phospholipid and plasma apoE levels (reported by others), together with high macrophage scavenger receptor AI/II mRNA, could inhibit accretion of cholesterol in the vessel wall in the 2 resistant strains.

Apolipoprotein E-epsilon4 genotype predicts a poor outcome in survivors of traumatic brain injury.

OBJECTIVE: To determine the ability of apolipoprotein E (APOE) genotypes to predict days of unconsciousness and a suboptimal functional outcome in traumatic brain injury (TBI) survivors. BACKGROUND: TBI is known to be associated with neuropsychological deficits and functional disability. Recent evidence indicates that APOE plays a pivotal role in CNS response to injury. METHODS: In this prospective study the authors determined the APOE genotypes and tested their ability to predict days of unconsciousness and functional outcome after at least 6 months in 69 survivors of TBI. A good functional outcome was defined as no dysarthria, behavioral abnormalities, or dysphasia; no severe cognitive abnormalities; and the ability to live independently. RESULTS: The odds ratio of more than 7 days of unconsciousness was 5.69 in those with the APOE-epsilon4 allele compared with those without the epsilon4 allele (95% CI, 1.69 to 20.0; p = 0.001). Only 1 of 27 subjects (3.7%) with the epsilon4 allele had a good functional outcome compared with 13 of 42 (31.0%) of those without the epsilon4 allele (p = 0.006). The OR of a suboptimal outcome (fair or unfavorable) was 13.93 for those with the epsilon4 allele compared with those without the allele after controlling for age and time of unconsciousness (95% CI, 1.45 to 133.97; p = 0.02). CONCLUSION: The results demonstrate a strong association between the APOE-epsilon4 allele and a poor clinical outcome, implying genetic susceptibility to the effect of brain injury. Additional studies of TBI patients are warranted to confirm their findings.

Activation of the recombination activating gene 1 (RAG-1) transcript in bone marrow of senescent C57BL/6 mice by recombinant interleukin-7.

The level of the recombination activating gene 1 (RAG-1) mRNA in bone marrow cells decreases to a minimal level by the age of 10 months. Recominbant interleukin-7 (rIL-7) is a potent proliferative stimulus for B cell progenitors and upregulates RAG-1 expression in lymphocyte precursors. To investigate the stimulatory effect of rIL-7 on the expression of RAG-1 in old mice, we compared the level of RAG-1 message in short-term bone marrow cultures of cells from mice aged 1 month and 18 months. We found similar levels of RAG-1 mRNA in bone marrow cells of young mice before and after 24 hours of incubation. No RAG-1 mRNA was detected in bone marrow cell cultures prepared from old mice after 24 hours of incubation. However, when rIL-7 was added to the culture medium, RAG-1 mRNA was detected after 24 hours of incubation and its level was similar to that measured in cells from young mice. The expression of RAG-1 was dose-dependent, with 20 ng of rIL-7 per 10(6) old nucleated cells yielding the maximal response. Our results indicate that despite the low or no RAG-1 expression in bone marrow cultures of old mice, the potential to activate RAG-1 in B-cell precursors is still present, and immunoglobulin heavy chain (V(H)D(H)J(H)) rearrangement may be enhanced by rIL7.

A common mutation A1298C in human methylenetetrahydrofolate reductase gene: association with plasma total homocysteine and folate concentrations.

Methylenetetrahydrofolate reductase (MTHFR) is one of the main regulatory enzymes of homocysteine metabolism. Previous studies revealed that a common mutation in MTHFR gene C677T is related to hyperhomocysteinemia and occlusive vascular pathology. In the current study, we determined the prevalence of a newly described mutation in the human MTHFR gene A1298C, and the already known C677T mutation, and related them to plasma total homocysteine and folate concentrations. We studied 377 Jewish subjects, including 190 men and 186 women aged 56.8 +/- 13 y (range 32-95 y). The frequency of the homozygotes for the A1298C and the C677T MTHFR mutations was common in the Jewish Israeli population (0.34 and 0.37, respectively). Subjects homozygous (TT) for the C677T mutation had significantly greater plasma total homocysteine concentrations (P < 0.01) than subjects without the mutation (CC). Homozygotes (CC) for the A1298C mutation did not have elevated plasma total homocysteine concentrations. Our study indicated that subjects with the 677CC/1298CC genotype had significantly lower concentrations (P < 0. 05) than those with a 677CC/1298AA genotype. Neither mutation (the A1298C and the C677T) was associated with established cardiovascular risk factors such as hypertension, elevated total cholesterol or body mass index.