Summary In yeast, worms and flies, an extra copy of the gene encoding the Sirtuin Sir2 increases metabolic efficiency, as does administration of polyphenols like resveratrol, thought to act through Sirtuins. But evidence that Sirtuin gain-of-function results in increased metabolic efficiency in mammals is limited. We generated transgenic mice with moderate overexpression of SirT1, designed to mimic the Sirtuin gain-of-function that improves metabolism in C.elegans. These mice exhibit normal insulin sensitivity, but decreased food intake and locomotor activity, resulting in decreased energy expenditure. However, in various models of insulin resistance and diabetes, SirT1 transgenics display improved glucose tolerance due to decreased hepatic glucose production and increased adiponectin levels, without changes in body weight or composition. We conclude that SirT1 gain-of-function primes the organism for metabolic adaptation to insulin resistance, increasing hepatic insulin sensitivity and decreasing whole-body energy requirements. These findings have important implications for Sirtuin-based therapies in humans.

Insulin integrates hepatic glucose and lipid metabolism, directing nutrients to storage as glycogen and triglyceride. In type 2 diabetes, levels of the former are low and the latter are exaggerated, posing a pathophysiologic and therapeutic conundrum. A branching model of insulin signaling, with FoxO1 presiding over glucose production and Srebp–1c regulating lipogenesis, provides a potential explanation. Here we illustrate an alternative mechanism that integrates glucose production and lipogenesis under the unifying control of FoxO. Liver–specific ablation of three FoxOs (L–FoxO1,3,4) prevents the induction of glucose–6–phosphatase and the repression of glucokinase during fasting, thus increasing lipogenesis at the expense of glucose production. We document a similar pattern in the early phases of diet-induced insulin resistance, and propose that FoxOs are required to enable the liver to direct nutritionally derived carbons to glucose vs. lipid metabolism. Our data underscore the heterogeneity of hepatic insulin resistance during progression from the metabolic syndrome to overt diabetes, and the conceptual challenge of designing therapies that curtail glucose production without promoting hepatic lipid accumulation.

Heart failure (HF) has been recognized as a common complication of diabetes, with a prevalence of up to 22% in individuals with diabetes and increasing incidence rates. Data also suggest that HF may develop in individuals with diabetes even in the absence of hypertension, coronary heart disease, or valvular heart disease and, as such, represents a major cardiovascular complication in this vulnerable population; HF may also be the first presentation of cardiovascular disease in many individuals with diabetes. Given that during the past decade, the prevalence of diabetes (particularly type 2 diabetes) has risen by 30% globally (with prevalence expected to increase further), the burden of HF on the health care system will continue to rise. The scope of this American Diabetes Association consensus report with designated representation from the American College of Cardiology is to provide clear guidance to practitioners on the best approaches for screening and diagnosing HF in individuals with diabetes or prediabetes, with the goal to ensure access to optimal, evidence-based management for all and to mitigate the risks of serious complications, leveraging prior policy statements by the American College of Cardiology and American Heart Association.

OBJECTIVESirtuin 1 (SIRT1) and its activator resveratrol are emerging as major regulators of metabolic processes. We investigate the site of resveratrol action on glucose metabolism and the contribution of SIRT1 to these effects. Because the arcuate nucleus in the mediobasal hypothalamus (MBH) plays a pivotal role in integrating peripheral metabolic responses to nutrients and hormones, we examined whether the actions of resveratrol are mediated at the MBH.RESEARCH DESIGN AND METHODSSprague Dawley (SD) male rats received acute central (MBH) or systemic injections of vehicle, resveratrol, or SIRT1 inhibitor during basal pancreatic insulin clamp studies. To delineate the pathway(s) by which MBH resveratrol modulates hepatic glucose production, we silenced hypothalamic SIRT1 expression using a short hairpin RNA (shRNA) inhibited the hypothalamic ATP-sensitive potassium (KATP) channel with glibenclamide, or selectively transected the hepatic branch of the vagus nerve while infusing resveratrol centrally.RESULTSOur studies show that marked improvement in insulin sensitivity can be elicited by acute administration of resveratrol to the MBH or during acute systemic administration. Selective inhibition of hypothalamic SIRT1 using a cell-permeable SIRT1 inhibitor or SIRT1-shRNA negated the effect of central and peripheral resveratrol on glucose production. Blockade of the KATP channel and hepatic vagotomy significantly attenuated the effect of central resveratrol on hepatic glucose production. In addition, we found no evidence for hypothalamic AMPK activation after MBH resveratrol administration.CONCLUSIONSTaken together, these studies demonstrate that resveratrol improves glucose homeostasis mainly through a central SIRT1-dependent pathway and that the MBH is a major site of resveratrol action.

The metabolism of lactate to pyruvate in the mediobasal hypothalamus (MBH) regulates hepatic glucose production. Because astrocytes and neurons are functionally linked by metabolic coupling through lactate transfer via the astrocyte-neuron lactate shuttle (ANLS), we reasoned that astrocytes might be involved in the hypothalamic regulation of glucose metabolism. To examine this possibility, we used the gluconeogenic amino acid proline, which is metabolized to pyruvate in astrocytes. Our results showed that increasing the availability of proline in rats either centrally (MBH) or systemically acutely lowered blood glucose. Pancreatic clamp studies revealed that this hypoglycemic effect was due to a decrease of hepatic glucose production secondary to an inhibition of glycogenolysis, gluconeogenesis, and glucose-6-phosphatase flux. The effect of proline was mimicked by glutamate, an intermediary of proline metabolism. Interestingly, proline’s action was markedly blunted by pharmacological inhibition of hypothalamic lactate dehydrogenase (LDH) suggesting that metabolic flux through LDH was required. Furthermore, short hairpin RNA–mediated knockdown of hypothalamic LDH-A, an astrocytic component of the ANLS, also blunted the glucoregulatory action of proline. Thus our studies suggest not only a new role for proline in the regulation of hepatic glucose production but also indicate that hypothalamic astrocytes are involved in the regulatory mechanism as well.

SUMMARY Obesity is associated with higher incidence of cancer but the predisposing mechanisms remain poorly understood. The NAD+–dependent deacetylase SirT1 orchestrates metabolism, cellular survival, and growth. To date, there is no unifying mechanism to explain the metabolic and tumor-related effects of SirT1. In this work, we demonstrate that genetic ablation of the endogenous inhibitor of SirT1, Deleted-in-Breast-Cancer-1 (Dbc1), unexpectedly results in obesity and insulin-resistance. Dbc1 deficiency promoted SirT1-dependent gain-of-function of stearoyl-coenzyme A desaturase 1 (Scd1), increasing plasma and tissue levels of unsaturated fatty acids. The metabolic abnormalities in Dbc1−/− mice were reversed by ablation of hepatic SirT1 or by inhibition of Scd1 activity. Furthermore, loss of Dbc1 impaired master tumor suppressor p53 activation and treatment of Scd1 inhibitor extended survival of tumorigenic TP53−/− mice by decreasing tumor-related death. Together, our findings illustrate a shared mechanism of obesity and tumor progression through hepatic SirT1 gain-of-function in a metabolic control step, with potential therapeutic implications.

<p>  </p> <p>Traditionally, the prevention and management of chronic complications in individuals with type 1 (T1D) and type 2 diabetes (T2D) has been focused on of nephropathy, retinopathy, neuropathy, and atherosclerotic cardiovascular disease (including ischemic heart disease, stroke or peripheral vascular disease) (1). However, heart failure (HF) has been recognized as a common complication of diabetes, with a prevalence of up to 22% in individuals with diabetes and increasing incidence rates (2–4). This recognition stems in part from trials focused on cardiovascular safety of newer drugs to treat diabetes. Data also suggest HF may develop in individuals with diabetes even in the absence of hypertension, coronary heart disease, or valvular heart disease and, as such, represents a major cardiovascular complication in this vulnerable population (5). Given that during the past decade, the prevalence of diabetes (particularly T2D) has risen by 30% globally (6) (with prevalence expected to increase further), the burden of HF on the health care system will continue to rise.</p> <p>The scope of this American Diabetes Association (ADA) consensus report with designated representation from the American College of Cardiology (ACC) is to provide clear guidance and to recommend best approaches to general internists, family physicians, and endocrinologists for HF screening, diagnosis, and management in individuals with T1D, T2D, or prediabetes to mitigate the risks of serious complications, leveraging prior policy statements by the ACC (7) and American Heart Association (AHA) (2). This consensus report was developed by the writing group convened by ADA with representation from ACC through a series of conference calls, emails, and independent work from March 2021 through March 2022. </p> <p>Traditionally, the prevention and management of chronic complications in individuals with type 1 (T1D) and type 2 diabetes (T2D) has been focused on of nephropathy, retinopathy, neuropathy, and atherosclerotic cardiovascular disease (including ischemic heart disease, stroke or peripheral vascular disease) (1). However, heart failure (HF) has been recognized as a common complication of diabetes, with a prevalence of up to 22% in individuals with diabetes and increasing incidence rates (2–4). This recognition stems in part from trials focused on cardiovascular safety of newer drugs to treat diabetes. Data also suggest HF may develop in individuals with diabetes even in the absence of hypertension, coronary heart disease, or valvular heart disease and, as such, represents a major cardiovascular complication in this vulnerable population (5). Given that during the past decade, the prevalence of diabetes (particularly T2D) has risen by 30% globally (6) (with prevalence expected to increase further), the burden of HF on the health care system will continue to rise.</p> <p>The scope of this American Diabetes Association (ADA) consensus report with designated representation from the American College of Cardiology (ACC) is to provide clear guidance and to recommend best approaches to general internists, family physicians, and endocrinologists for HF screening, diagnosis, and management in individuals with T1D, T2D, or prediabetes to mitigate the risks of serious complications, leveraging prior policy statements by the ACC (7) and American Heart Association (AHA) (2). This consensus report was developed by the writing group convened by ADA with representation from ACC through a series of conference calls, emails, and independent work from March 2021 through March 2022. </p>

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