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Type 1 diabetes affects 20 million patients worldwide. Insulin is the primary and commonly the sole therapy for type 1 diabetes. However, only a minority of patients attain the targeted glucose control and reduced adverse events. We tested urocortin 2 gene transfer as single-agent therapy for insulin deficiency using two mouse models. Urocortin 2 gene transfer reduced blood glucose for months after a single intravenous injection, through increased skeletal muscle insulin sensitivity, increased insulin release in response to glucose stimulation, and increased plasma insulin levels before and during euglycemic clamp. The combined increases in both insulin availability and sensitivity resulted in improved glycemic indices-events that were not anticipated in these insulin-deficient models. In addition, urocortin 2 gene transfer reduced ocular manifestations of long-standing insulin deficiency such as vascular leak and improved retinal function. Finally, mortality was reduced by urocortin 2 gene transfer. The mechanisms for these beneficial effects included increased activities of AMP-activated protein kinase and Akt (protein kinase B) in skeletal muscle, increased skeletal muscle glucose uptake, and increased insulin release. These data suggest that urocortin 2 gene transfer may be a viable therapy for new onset type 1 diabetes and might reduce insulin needs in later stage disease.

Maintaining a healthy body weight requires an exquisite balance between energy intake and energy expenditure. To understand the genetic and environmental factors that contribute to the regulation of body weight, an important first step is to establish the normal range of metabolic values and primary sources contributing to variability. Energy metabolism is measured by powerful and sensitive indirect calorimetry devices. Analysis of nearly 10,000 wild-type mice from two large-scale experiments revealed that the largest variation in energy expenditure is due to body composition, ambient temperature, and institutional site of experimentation. We also analyze variation in 2329 knockout strains and establish a reference for the magnitude of metabolic changes. Based on these findings, we provide suggestions for how best to design and conduct energy balance experiments in rodents. These recommendations will move us closer to the goal of a centralized physiological repository to foster transparency, rigor and reproducibility in metabolic physiology experimentation.

ObjectiveAging is associated with impaired insulin sensitivity and increased prevalence of type 2 diabetes. However, it remains unclear whether aging-associated insulin resistance is due to increased adiposity or other age-related factors. To address this question, the impact of aging on insulin sensitivity was investigated independently of changes in body composition.MethodsCohorts of mice aged 4 to 8 months ("young") and 18 to 27 months ("aged") exhibiting similar body composition were characterized for glucose metabolism on chow and high-fat diets. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp analyses. The relationship between aging and insulin resistance in humans was investigated in 1,250 nondiabetic Mexican Americans who underwent hyperinsulinemic-euglycemic clamps.ResultsIn mice with similar body composition, age had no detrimental effect on plasma glucose and insulin levels. While aging did not diminish glucose tolerance, hyperinsulinemic-euglycemic clamps demonstrated impaired insulin sensitivity and reduced insulin clearance in aged mice on chow and high-fat diets. Consistent with results in the mouse, age remained an independent determinant of insulin resistance after adjustment for body composition in Mexican American males.ConclusionsThis study demonstrates that in addition to altered body composition, adiposity-independent mechanisms also contribute to aging-associated insulin resistance in mice and humans.

Natriuretic regulation of extracellular fluid volume homeostasis includes suppression of the renin-angiotensin-aldosterone system, pressure natriuresis, and reduced renal nerve activity, actions that concomitantly increase urinary [Na.sup.+] excretion and lead to increased urine volume. The resulting natriuresis-driven diuretic water loss is assumed to control the extracellular volume. Here, we have demonstrated that urine concentration, and therefore regulation of water conservation, is an important control system for urine formation and extracellular volume homeostasis in mice and humans across various levels of salt intake. We observed that the renal concentration mechanism couples natriuresis with correspondent renal water reabsorption, limits natriuretic osmotic diuresis, and results in concurrent extracellular volume conservation and concentration of salt excreted into urine. This water-conserving mechanism of dietary salt excretion relies on urea transporter-driven urea recycling by the kidneys and on urea production by liver and skeletal muscle. The energy-intense nature of hepatic and extrahepatic urea osmolyte production for renal water conservation requires reprioritization of energy and substrate metabolism in liver and skeletal muscle, resulting in hepatic ketogenesis and glucocorticoid- driven muscle catabolism, which are prevented by increasing food intake. This natriuretic-ureotelic, water-conserving principle relies on metabolism-driven extracellular volume control and is regulated by concerted liver, muscle, and renal actions., Introduction Renal excretion of dietary [Na.sup.+] under high-salt conditions occurs by a natriuretic principle. The assumption is that high salt intake triggers thirst and thereby increases fluid intake, which expands [...]

The chronic inflammatory state that accompanies obesity is a major contributor to insulin resistance and other dysfunctional adaptations in adipose tissue. Cellular and secreted factors promote the inflammatory milieu of obesity, but the transcriptional pathways that drive these processes are not well described. Although the canonical inflammatory transcription factor NF-κB is considered to be the major driver of adipocyte inflammation, members of the interferon regulatory factor (IRF) family may also play a role in this process. Here, we determined that IRF3 expression is upregulated in the adipocytes of obese mice and humans. Signaling through TLR3 and TLR4, which lie upstream of IRF3, induced insulin resistance in murine adipocytes, while IRF3 knockdown prevented insulin resistance. Furthermore, improved insulin sensitivity in IRF3-deficient mice was associated with reductions in intra-adipose and systemic inflammation in the high fat-fed state, enhanced browning of subcutaneous fat, and increased adipose expression of GLUT4. Taken together, the data indicate that IRF3 is a major transcriptional regulator of adipose inflammation and is involved in maintaining systemic glucose and energy homeostasis., Introduction One of the major concepts emerging from the last 2 decades of metabolism research is the notion of 'metainflammation,' the state of chronic low-grade inflammation that develops during periods [...]

Type 2 diabetes (T2D) is among the most common and costly disorders worldwide (1). The goal of current medical management for T2D is to transiently ameliorate hyperglycemia through daily dosing of one or more antidiabetic drugs. Hypoglycemia and weight gain are common side effects of therapy, and sustained disease remission is not obtainable with nonsurgical approaches. On the basis of the potent glucose-lowering response elicited by activation of brain fibroblast growth factor (FGF) receptors (2-4), we explored the antidiabetic efficacy of centrally administered FGF1, which, unlike other FGF peptides, activates all FGF receptor subtypes (5). We report that a single intracerebroventricular injection of FGF1 at a dose one-tenth of that needed for antidiabetic efficacy following peripheral injection induces sustained diabetes remission in both mouse and rat models of T2D. This antidiabetic effect is not secondary to weight loss, does not increase the risk of hypoglycemia, and involves a novel and incompletely understood mechanism for increasing glucose clearance from the bloodstream. We conclude that the brain has an inherent potential to induce diabetes remission and that brain FGF receptors are potential pharmacological targets for achieving this goal., Growing evidence points to the brain as a potential target for the treatment of T2D (6,7). In rodent models of T2D, hyperglycemia can be ameliorated transiently by either systemic or [...]

Benziane B, Bjornholm M, Lantier L, Viollet B, Zierath JR, Chibalin AV. AMP-activated protein kinase activator A-769662 is an inhibitor of the [Na.sup.+]-[K.sup.+]-ATPase. Am J Physiol Cell Physiol 297: C1554-C1566, 2009. First published October 14, 2009; doi: 10.1152/ajpcell.00010.2009.--Muscle contraction and metabolic stress are potent activators of AMP-activated protein kinase (AMPK). AMPK restores energy balance by activating processes that produce energy while inhibiting those that consume energy. The role of AMPK in the regulation of active ion transport is unclear. Our aim was to determine the effect of the AMPK activator A-769662 on [Na.sup.+][-K.sup.+]-ATPase function in skeletal muscle cells. Short-term incubation of differentiated rat L6 myotubes with 100 [micro]M A-769662 increased AMPK and acetyl-CoA carboxylase (ACC) phosphorylation in parallel with decreased [Na.sup.+][-K.sup.+]-ATPase [[alpha].sub.1]-subunit abundance at the plasma membrane and ouabain-sensitive [.sup.86][Rb.sup.+] uptake. Notably, the effect of A-769662 on [Na.sup.+][-K.sup.+]-ATPase was similar in muscle cells that do not express AMPK [[alpha].sub.1]- and [[alpha].sub.2]- catalytic subunits. A-769662 directly inhibits the [[alpha].sub.1]-isoform of the [Na.sup.+][- K.sup.+]-ATPase, purified from rat and human kidney cells in vitro with [IC.sub.50] 57 [micro]M and 220 [micro]M, respectively. Inhibition of the [Na.sup.+][-K.sup.+]-ATPase by 100 [micro]M ouabain decreases sodium pump activity and cell surface abundance, similar to the effect of A-769662, without affecting AMPK and ACC phosphorylation. In conclusion, the AMPK activator A-769662 inhibits [Na.sup.+][-K.sup.+]-ATPase activity and decreases the sodium pump cell surface abundance in L6 skeletal muscle cells. The effect of A-769662 on sodium pump is due to direct inhibition of the [Na.sup.+][-K.sup.+]-ATPase activity, rather than AMPK activation. This AMPK-independent effect on [Na.sup.+][-K.sup.+]-ATPase calls into question the use of A-769662 as a specific AMPK activator for metabolic studies. ouabain; skeletal muscle cells doi: 10.1152/ajpcell.00010.2009

Background: Negative emotional states are associated with the initiation and maintenance of alcohol use and drive relapse to drinking during withdrawal and protracted abstinence. Physical exercise is correlated with decreased negative affective symptoms, although a direct relationship between drinking patterns and exercise level has not been fully elucidated. Methods: We incorporated intermittent running wheel access into a chronic continuous access, two‐bottle choice alcohol drinking model in female C57BL/6J mice. Wheel access was granted intermittently once mice established a preference for alcohol over water. After 6 weeks, alcohol was removed (forced abstinence) and mice were given continuous access to unlocked or locked wheels. Negative affect‐like behavior, home cage behavior, and metabolic activity were measured during protracted abstinence. Results: Wheel access shifted drinking patterns in the mice, increasing drinking when the wheel was locked, and decreasing drinking when unlocked. Moreover, alcohol preference and consumption were strongly negatively correlated with the amount of running. An assessment of negative affect‐like behavior in abstinence via the novelty suppressed feeding and saccharin preference tests (SPT) showed that unlimited wheel access mitigated abstinence‐induced latency increases. Mice in abstinence also spent more time sleeping during the active dark cycle than control mice, providing additional evidence for abstinence‐induced anhedonia‐ and depression‐like behavior. Furthermore, running wheel access in abstinence decreased dark cycle sleep to comparable alcohol‐ and wheel‐naïve mice. Given the positive impact of exercise and the negative impact of alcohol on metabolic health, we compared metabolic phenotypes of alcohol‐abstinent mice with and without wheel access. Wheel access increased energy expenditure, carbon dioxide production, and oxygen consumption, providing a potential metabolic mechanism through which wheel access improves affective state. Conclusions: This study suggests that including exercise in AUD treatment regimens has the potential to reduce drinking, improve affective state during abstinence and could serve as a non‐pharmacological approach to prevent the development of an AUD in high‐risk individuals. [ABSTRACT FROM AUTHOR]