Biomedical subjects

Jake A Kushner

Publications and source records attributed to Jake A Kushner.

11 recordsLinked to original sources

PubMed2006

Beta-cell growth: an unusual paradigm of organogenesis that is cyclin D2/Cdk4 dependent.

Improved understanding of the signals that regulate growth and maintenance of adult beta-cells remains one of the main challenges in diabetes research. However, new advances in identifying the specific components involved in G1 cell cycle progression of beta-cells suggest that the molecular determinants of this pathway could ultimately be revealed. We find that cyclin D2, and to a minor degree cyclin D1, are required for adult beta-cell growth. Our observations complement previous data regarding cdk4, and suggest that mitogenic signals could act via this pathway to influence acquisition of adult beta-cell mass. Although cyclin D2/cdk4 activity is critically important for beta-cell growth, it was unclear how much ongoing replication is required to maintain beta-cell mass. Our recent long-term beta-cell labeling studies reveal that adult beta-cells could conceivably live for the life of the organism. This new paradigm of long-lived beta-cells challenges previous notions of rapid turnover of adult beta-cell mass. Thus, much remains to be learned in order to expand adult beta-cell mass in diabetes patients.

Aging↗

PubMed2006

Effects of autoimmunity and immune therapy on beta-cell turnover in type 1 diabetes.

beta-Cell mass can expand in response to demand: during pregnancy, in the setting of insulin resistance, or after pancreatectomy. It is not known whether similar beta-cell hyperplasia occurs following immune therapy of autoimmune diabetes, but the clinical remission soon after diagnosis and the results of recent immune therapy studies suggest that beta-cell recovery is possible. We studied changes in beta-cell replication, mass, and apoptosis in NOD mice during progression to overt diabetes and following immune therapy with anti-CD3 monoclonal antibodies (mAbs) or immune regulatory T-cells (Tregs). beta-Cell replication increases in pre-diabetic mice, after adoptive transfer of diabetes with increasing islet inflammation but before an increase in blood glucose concentration or a significant decrease in beta-cell mass. The pathogenic cells are responsible for increasing beta-cell replication because replication was reduced during diabetes remission induced by anti-CD3 mAb or Tregs. beta-Cell replication stimulated by the initial inflammatory infiltrate results in increased production of new beta-cells after immune therapy and increased beta-cell area, but the majority of this increased beta-cell area represents regranulated beta-cells rather than newly produced cells. We conclude that beta-cell replication is closely linked to the islet inflammatory process. A significant proportion of degranulated beta-cells remain, at the time of diagnosis of diabetes, that can recover after metabolic correction of hyperglycemia. Correction of the beta-cell loss in type 1 diabetes will, therefore, require strategies that target both the immunologic and cellular mechanisms that destroy and maintain beta-cell mass.

Animals↗

PubMed2005

Phosphatase and tensin homolog regulation of islet growth and glucose homeostasis.

The Irs2 branch of the insulin/insulin-like growth factor signaling cascade activates the phosphatidylinositol 3-kinase --> Akt --> Foxo1 cascade in many tissues, including hepatocytes and pancreatic beta-cells. The 3'-lipid phosphatase Pten ordinarily attenuates this cascade; however, its influence on beta-cell growth or function is unknown. To determine whether decreased Pten expression could restore beta-cell function and prevent diabetes in Irs2(-/-) mice, we generated wild type or Irs2 knock-out mice that were haploinsufficient for Pten (Irs2(-/-)::Pten(+/-)). Irs2(-/-) mice develop diabetes by 3 months of age as beta-cell mass declined progressively until insulin production was lost. Pten insufficiency increased peripheral insulin sensitivity in wild type and Irs2(-/-) mice and increased Akt and Foxo1 phosphorylation in the islets. Glucose tolerance improved in the Pten(+/-) mice, although beta-cell mass and circulating insulin levels decreased. Compared with Irs2(-/-) mice, the Irs2(-/-)::Pten(+/-) mice displayed nearly normal glucose tolerance and survived without diabetes, because normal but small islets produced sufficient insulin until the mice died of lymphoproliferative disease at 12 months age. Thus, steps to enhance phosphatidylinositol 3-kinase signaling can promote beta-cell growth, function, and survival without the Irs2 branch of the insulin/insulin-like growth factor signaling cascade.

Animals↗

PubMed2005

Insulin receptor substrate 2 is essential for maturation and survival of photoreceptor cells.

Insulin receptor substrates (Irs-proteins) integrate signals from the insulin and insulin-like growth factor-1 (IGF1) receptors with other processes to control cellular growth, function, and survival. Here, we show that Irs2 promoted the maturation and survival of photoreceptors in the murine retina immediately after birth. Irs2 was mainly localized to the outer plexiform layer as well as to photoreceptor inner segments. It was also seen in ganglion cells and inner plexiform layer but in smaller amounts. Compared with control littermates, Irs2 knock-out mice lose 10% of their photoreceptors 1 week after birth and up to 50% by 2 weeks of age as a result of increased apoptosis. The surviving photoreceptor cells developed short organized segments, which displayed proportionally diminished but otherwise normal electrical function. However, IGF1-stimulated Akt phosphorylation was barely detected, and cleaved/activated caspase-3 was significantly elevated in isolated retinas of Irs2-/- mice. When diabetes was prevented, which allowed the Irs2-/- mice to survive for 2 years, most photoreceptor cells were lost by 16 months of age. Because apoptosis is the final common pathway in photoreceptor degeneration, pharmacological strategies that increase Irs2 expression or function in photoreceptor cells could be a general treatment for blinding diseases such as retinitis pigmentosa.

Age Factors↗

PubMed2005

Cyclins D2 and D1 are essential for postnatal pancreatic beta-cell growth.

Regulation of adult beta-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, beta-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 beta-cell mass decreased after birth. Thus, cyclins D2 and D1 were essential for beta-cell expansion in adult mice. Strategies to tightly regulate D-type cyclin activity in beta cells could prevent or cure diabetes.

Animals↗

PubMed2005

Very slow turnover of beta-cells in aged adult mice.

Although many signaling pathways have been shown to promote beta-cell growth, surprisingly little is known about the normal life cycle of preexisting beta-cells or the signaling pathways required for beta-cell survival. Adult beta-cells have been speculated to have a finite life span, with ongoing adult beta-cell replication throughout life to replace lost cells. However, little solid evidence supports this idea. To more accurately measure adult beta-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 beta-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 approximately 1,400 adult beta-cells were found to undergo replication per day. We conclude that adult beta-cells are very long lived.

Aging↗

PubMed2004

Dysregulation of insulin receptor substrate 2 in beta cells and brain causes obesity and diabetes.

The molecular link between obesity and beta cell failure that causes diabetes is difficult to establish. Here we show that a conditional knockout of insulin receptor substrate 2 (Irs2) in mouse pancreas beta cells and parts of the brain--including the hypothalamus--increased appetite, lean and fat body mass, linear growth, and insulin resistance that progressed to diabetes. Diabetes resolved when the mice were between 6 and 10 months of age: functional beta cells expressing Irs2 repopulated the pancreas, restoring sufficient beta cell function to compensate for insulin resistance in the obese mice. Thus, Irs2 signaling promotes regeneration of adult beta cells and central control of nutrient homeostasis, which can prevent obesity and diabetes in mice.

Animals↗

PubMed2004

Islet-sparing effects of protein tyrosine phosphatase-1b deficiency delays onset of diabetes in IRS2 knockout mice.

Protein tyrosine phosphatase-1b (Ptp1b) inhibits insulin and leptin signaling by dephosphorylating specific tyrosine residues in their activated receptor complexes. Insulin signals are mediated by tyrosine phosphorylation of the insulin receptor and its downstream targets, such as Irs1 and Irs2. Irs2 plays an especially important role in glucose homeostasis because it mediates some peripheral actions of insulin and promotes pancreatic beta-cell function. To determine whether the deletion of Ptp1b compensates for the absence of Irs2, we analyzed mice deficient in both Ptp1b and Irs2. Pancreatic beta-cell area decreased in Ptp1b(-/-) mice, consistent with decreased insulin requirements owing to increased peripheral insulin sensitivity. By contrast, peripheral insulin sensitivity and beta-cell area increased in Irs2(-/-)::Ptp1b(-/-) mice, which improved glucose tolerance in Irs2(-/-)::Ptp1b(-/-) mice and delayed diabetes until 3 months of age. However, beta-cell function eventually failed to compensate for absence of Irs2. Our studies demonstrate a novel role for Ptp1b in regulating beta-cell homeostasis and indicate that Ptp1b deficiency can partially compensate for lack of Irs2.

Animals↗

PubMed2003

Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation.

Insulin resistance and diabetes might promote neurodegenerative disease, but a molecular link between these disorders is unknown. Many factors are responsible for brain growth, patterning, and survival, including the insulin-insulin-like growth factor (IGF)-signaling cascades that are mediated by tyrosine phosphorylation of insulin receptor substrate (IRS) proteins. Irs2 signaling mediates peripheral insulin action and pancreatic beta-cell function, and its failure causes diabetes in mice. In this study, we reveal two important roles for Irs2 signaling in the mouse brain. First, disruption of the Irs2 gene reduced neuronal proliferation during development by 50%, which dissociated brain growth from Irs1-dependent body growth. Second, neurofibrillary tangles containing phosphorylated tau accumulated in the hippocampus of old Irs2 knock-out mice, suggesting that Irs2 signaling is neuroprotective. Thus, dysregulation of the Irs2 branch of the insulin-Igf-signaling cascade reveals a molecular link between diabetes and neurodegenerative disease.

Age Factors↗

PubMed2002

Pdx1 restores beta cell function in Irs2 knockout mice.

The homeodomain transcription factor Pdx1 is required for pancreas development, including the differentiation and function of beta cells. Mutations in Pdx1 or upstream hepatocyte nuclear factors cause autosomal forms of early-onset diabetes (maturity-onset diabetes of the young [MODY]). In mice, the Irs2 branch of the insulin/Igf signaling system mediates peripheral insulin action and pancreatic beta cell growth and function. To investigate whether beta cell failure in Irs2(-/-) mice might be related to dysfunction of MODY-related transcription factors, we measured the expression of Pdx1 in islets from young Irs2(-/-) mice. Before the onset of diabetes, Pdx1 was reduced in islets from Irs2(-/-) mice, whereas it was expressed normally in islets from wild-type or Irs1(-/-) mice, which do not develop diabetes. Whereas male Irs2(-/-)Pdx1(+/+) mice developed diabetes between 8 and 10 weeks of age, haploinsufficiency for Pdx1 caused diabetes in newborn Irs2(-/-) mice. By contrast, transgenic expression of Pdx1 restored beta cell mass and function in Irs2(-/-) mice and promoted glucose tolerance throughout life, as these mice survived for at least 20 months without diabetes. Our results suggest that dysregulation of Pdx1 might represent a common link between ordinary type 2 diabetes and MODY.

Animals↗

PubMedDate not supplied

Effects of dietary glycaemic index on adiposity, glucose homoeostasis, and plasma lipids in animals.

BACKGROUND: Clinical studies suggest a role for dietary glycaemic index (GI) in bodyweight regulation and diabetes risk. However, partly because manipulation of GI can produce changes in potentially confounding dietary factors such as fibre content, palatability, and energy density, its relevance to human health remains controversial. This study examined the independent effects of GI in animals. METHODS: Partially pancreatectomised male Sprague-Dawley rats were given diets with identical nutrients, except for the type of starch: high-GI (n=11) or low-GI (n=10). The animals were fed in a controlled way to maintain the same mean bodyweight in the two groups for 18 weeks. Further experiments examined the effects of GI in rats in a cross-over design and C57BL/6J mice in a parallel design. FINDINGS: Despite having similar mean bodyweight (547.9 [SE 13.4] vs 549.2 [15.2] g), rats given high-GI food had more body fat (97.8 [13.6] vs 57.3 [7.2] g; p=0.0152) and less lean body mass (450.1 [9.6] vs 491.9 [11.7] g; p=0.0120) than those given low-GI food. The high-GI group also had greater increases over time in the areas under the curve for blood glucose and plasma insulin after oral glucose, lower plasma adiponectin concentrations, higher plasma triglyceride concentrations, and severe disruption of islet-cell architecture. Mice on the high-GI diet had almost twice the body fat of those on the low-GI diet after 9 weeks. INTERPRETATION: These findings provide a mechanistic basis for interpretation of studies of GI in human beings. RELEVANCE TO PRACTICE: The term GI describes how a food, meal, or diet affects blood sugar during the postprandial period. GI as an independent factor can cause obesity and increase risks of diabetes and heart disease in animals. Use of low-GI diets in prevention and treatment of human disease merits thorough examination.

Adiponectin↗