Reduced insulin-like signaling extends the life span of Caenorhabditis elegans and Drosophila . Here, we show that, in mice, less insulin receptor substrate–2 (Irs2) signaling throughout the body or just in the brain extended life span up to 18%. At 22 months of age, brain-specific Irs2 knockout mice were overweight, hyperinsulinemic, and glucose intolerant; however, compared with control mice, they were more active and displayed greater glucose oxidation, and during meals they displayed stable superoxide dismutase–2 concentrations in the hypothalamus. Thus, less Irs2 signaling in aging brains can promote healthy metabolism, attenuate meal-induced oxidative stress, and extend the life span of overweight and insulin-resistant mice.

Although many signaling pathways have been shown to promote ␤-cell growth, surprisingly little is known about the normal life cycle of preexisting ␤-cells or the signaling pathways required for ␤-cell survival. Adult ␤-cells have been speculated to have a finite life span, with ongoing adult ␤-cell replication throughout life to replace lost cells. However, little solid evidence supports this idea. To more accurately measure adult ␤-cell turnover, we performed continuous long-term labeling of proliferating cells with the DNA precursor analog 5-bromo-2-deoxyuridine (BrdU) in 1-year-old mice. We show that ␤-cells of aged adult mice have extremely low rates of replication, with minimal evidence of turnover. Although some pancreatic components acquired BrdU label in a linear fashion, only 1 in ϳ1,400 adult ␤-cells were found to undergo replication per day. We conclude that adult ␤-cells are very long lived. Diabetes 54: 2557-2567, 2005 I nadequate islet mass is a central finding in both type 1 and type 2 diabetes, resulting in an absolute or relative insulin deficiency and subsequent metabolic complications (1-3). Over the past decade, much has been learned about the specific signaling pathways that direct embryonic islet development (4) and postnatal islet growth (5). To compensate for increased metabolic demands, adult islet mass increases dramatically over the first year of life in rodents (6) and may represent growth within preexisting islets because islet density does not typically increase as mice age (7,8). It has been known for some time that adult ␤-cell growth is dependent on cyclindependent kinase-4 (9). Recently, we (10) and others (11) showed that cyclins D2 and D1 are the likely partners with cyclin-dependent kinase-4 to promote G 1 cell cycle progression in adult ␤-cells. Remarkably, new evidence suggests that much of adult ␤-cell growth may occur by replication of insulin-positive cells and not by ␤-cell neogenesis (12). However, it is possible that ␤-cell neogenesis may exist under some circumstances (13,14). Surprisingly little is known about the factors that promote adult ␤-cell survival, although some amount of ␤-cell apoptosis occurs in normal islets (15) as well as in pathological states (16). Although the absolute ␤-cell death rate is unknown, ␤-cell death appears to be a rare event. Supporting this notion, ␤-cell area increases severalfold throughout adulthood, despite an apparent decline in daily proliferation rate (6,17).Despite the lack of direct evidence, it has been largely assumed that ␤-cells have a finite life span, with dying cells replenished by new ␤-cells on an ongoing basis (12,14,17). One method of estimating cell life span is to measure the growth of total cell populations and cellular proliferation rate. In this model, the cell turnover rate is reflected by the proportion of cellular proliferation that does not contribute to cell population growth. In the simplest example of a stable population of cells with no net growth, cellular proliferation must be explained by ongoing lo...

Regulation of adult ␤-cell mass in pancreatic islets is essential to preserve sufficient insulin secretion in order to appropriately regulate glucose homeostasis. In many tissues mitogens influence development by stimulating D-type cyclins (D1, D2, or D3) and activating cyclin-dependent kinases (CDK4 or CDK6), which results in progression through the G 1 phase of the cell cycle. Here we show that cyclins D2 and D1 are essential for normal postnatal islet growth. In adult murine islets basal cyclin D2 mRNA expression was easily detected, while cyclin D1 was expressed at lower levels and cyclin D3 was nearly undetectable. Prenatal islet development occurred normally in cyclin D2 ؊/؊ or cyclin D1 ؉/؊ D2 ؊/؊ mice. However, ␤-cell proliferation, adult mass, and glucose tolerance were decreased in adult cyclin D2 ؊/؊ mice, causing glucose intolerance that progressed to diabetes by 12 months of age. Although cyclin D1 ؉/؊ mice never developed diabetes, life-threatening diabetes developed in 3-month-old cyclin D1 ؊/؉ D2 ؊/؊ mice as ␤-cell mass decreased after birth. Thus, cyclins D2 and D1 were essential for ␤-cell expansion in adult mice. Strategies to tightly regulate D-type cyclin activity in ␤ cells could prevent or cure diabetes.