Glucose intolerance in aging is mediated by the Gpcpd1-GPC metabolic axis

Skeletal muscle plays a central role in the regulation of systemic metabolism during lifespan. With aging, muscle mediated metabolic homeostasis is perturbed, contributing to the onset of multiple chronic diseases. Our knowledge on the mechanisms responsible for this age-related perturbation is limited, as it is difficult to distinguish between correlation and causality of molecular changes in muscle aging. Glycerophosphocholine phosphodiesterase 1 (GPCPD1) is a highly abundant muscle enzyme responsible for the hydrolysis of the lipid glycerophosphocholine (GPC). The physiological function of GPCPD1 remained largely unknown. Here, we report that the GPCPD1-GPC metabolic pathway is dramatically perturbed in the aged muscle. Muscle-specific inactivation of Gpcpd1 resulted in severely affected glucose metabolism, without affecting muscle development. This pathology was muscle specific and did not occur in white fat-, brown fat- and liver-specific Gpcpd1 deficient mice. Moreover, in the muscle specific mutant mice, glucose intolerance was markedly accelerated under high sugar and high fat diet. Mechanistically, Gpcpd1 deficiency results in accumulation of GPC, without any other significant changes in the global lipidome. This causes an aged-like transcriptomic signature in young Gpcpd1 deficient muscles, changes in myofiber osmolarity, and impaired insulin signaling. Finally, we report that GPC levels are markedly perturbed in muscles from both aged humans and patients with Type 2 diabetes. These results identify the GPCPD1-GPC metabolic pathway as critical to muscle aging and age-associated glucose intolerance.

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Aging and insulin secretion

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00366.2002 ◽

2003 ◽

Vol 284 (1) ◽

pp. E7-E12 ◽

Cited By ~ 233

Author(s):

Annette M. Chang ◽

Jeffrey B. Halter

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Older People ◽

Glucose Intolerance ◽

Therapeutic Interventions ◽

Β Cell ◽

Insulin Levels ◽

Cell Dysfunction ◽

Age Related

Glucose tolerance progressively declines with age, and there is a high prevalence of type 2 diabetes and postchallenge hyperglycemia in the older population. Age-related glucose intolerance in humans is often accompanied by insulin resistance, but circulating insulin levels are similar to those of younger people. Under some conditions of hyperglycemic challenge, insulin levels are lower in older people, suggesting β-cell dysfunction. When insulin sensitivity is controlled for, insulin secretory defects have been consistently demonstrated in aging humans. In addition, β-cell sensitivity to incretin hormones may be decreased with advancing age. Impaired β-cell compensation to age-related insulin resistance may predispose older people to develop postchallenge hyperglycemia and type 2 diabetes. An improved understanding of the metabolic alterations associated with aging is essential for the development of preventive and therapeutic interventions in this population at high risk for glucose intolerance.

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Effect of Physical Activity on Age-Related Glucose Intolerance

Clinics in Geriatric Medicine ◽

10.1016/s0749-0690(18)30585-8 ◽

1990 ◽

Vol 6 (4) ◽

pp. 849-863 ◽

Cited By ~ 12

Author(s):

Ami Laws ◽

Gerald M. Reaven

Keyword(s):

Physical Activity ◽

Glucose Intolerance ◽

Age Related

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Age-Related Trends in the Prevalence of Type 2 Diabetes among Japanese and White and Black American Adults

10.29011/2577-2252.100042 ◽

2020 ◽

Keyword(s):

Type 2 Diabetes ◽

Black American ◽

Age Related

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Lysosomes, Autophagy, and Hormesis in Cell Physiology, Pathology, and Age-Related Disease

Dose-Response ◽

10.1177/1559325820934227 ◽

2020 ◽

Vol 18 (3) ◽

pp. 155932582093422 ◽

Cited By ~ 2

Author(s):

Michael N. Moore

Keyword(s):

Intracellular Signaling ◽

Adenosine Monophosphate ◽

Target Of Rapamycin ◽

Cell Physiology ◽

Mechanistic Target Of Rapamycin ◽

Age Related ◽

Mechanistic Basis ◽

The Many ◽

Mtor Complex 1

Autophagy has been strongly linked with hormesis, however, it is only relatively recently that the mechanistic basis underlying this association has begun to emerge. Lysosomal autophagy is a group of processes that degrade proteins, protein aggregates, membranes, organelles, segregated regions of cytoplasm, and even parts of the nucleus in eukaryotic cells. These degradative processes are evolutionarily very ancient and provide a survival capability for cells that are stressed or injured. Autophagy and autophagic dysfunction have been linked with many aspects of cell physiology and pathology in disease processes; and there is now intense interest in identifying various therapeutic strategies involving its regulation. The main regulatory pathway for augmented autophagy is the mechanistic target of rapamycin (mTOR) cell signaling, although other pathways can be involved, such as 5′-adenosine monophosphate-activated protein kinase. Mechanistic target of rapamycin is a key player in the many highly interconnected intracellular signaling pathways and is responsible for the control of cell growth among other processes. Inhibition of mTOR (specifically dephosphorylation of mTOR complex 1) triggers augmented autophagy and the search is on the find inhibitors that can induce hormetic responses that may be suitable for treating many diseases, including many cancers, type 2 diabetes, and age-related neurodegenerative conditions.

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A Narrative Review on Sarcopenia in Type 2 Diabetes Mellitus: Prevalence and Associated Factors

Nutrients ◽

10.3390/nu13010183 ◽

2021 ◽

Vol 13 (1) ◽

pp. 183

Author(s):

Anna Izzo ◽

Elena Massimino ◽

Gabriele Riccardi ◽

Giuseppe Della Pepa

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Elderly Population ◽

The Elderly ◽

Narrative Review ◽

Macrovascular Complications ◽

Diabetic Patients ◽

Age Related

Type 2 diabetes mellitus (T2DM) represents a major health burden for the elderly population, affecting approximately 25% of people over the age of 65 years. This percentage is expected to increase dramatically in the next decades in relation to the increased longevity of the population observed in recent years. Beyond microvascular and macrovascular complications, sarcopenia has been described as a new diabetes complication in the elderly population. Increasing attention has been paid by researchers and clinicians to this age-related condition—characterized by loss of skeletal muscle mass together with the loss of muscle power and function—in individuals with T2DM; this is due to the heavy impact that sarcopenia may have on physical and psychosocial health of diabetic patients, thus affecting their quality of life. The aim of this narrative review is to provide an update on: (1) the risk of sarcopenia in individuals with T2DM, and (2) its association with relevant features of patients with T2DM such as age, gender, body mass index, disease duration, glycemic control, presence of microvascular or macrovascular complications, nutritional status, and glucose-lowering drugs. From a clinical point of view, it is necessary to improve the ability of physicians and dietitians to recognize early sarcopenia and its risk factors in patients with T2DM in order to make appropriate therapeutic approaches able to prevent and treat this condition.

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Hyperinsulinemia and Its Pivotal Role in Aging, Obesity, Type 2 Diabetes, Cardiovascular Disease and Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22157797 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7797

Author(s):

Joseph A. M. J. L. Janssen

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Insulin Secretion ◽

Early Stage ◽

Insulin Clearance ◽

Future Research ◽

Age Related ◽

Hepatic Insulin Clearance

For many years, the dogma has been that insulin resistance precedes the development of hyperinsulinemia. However, recent data suggest a reverse order and place hyperinsulinemia mechanistically upstream of insulin resistance. Genetic background, consumption of the “modern” Western diet and over-nutrition may increase insulin secretion, decrease insulin pulses and/or reduce hepatic insulin clearance, thereby causing hyperinsulinemia. Hyperinsulinemia disturbs the balance of the insulin–GH–IGF axis and shifts the insulin : GH ratio towards insulin and away from GH. This insulin–GH shift promotes energy storage and lipid synthesis and hinders lipid breakdown, resulting in obesity due to higher fat accumulation and lower energy expenditure. Hyperinsulinemia is an important etiological factor in the development of metabolic syndrome, type 2 diabetes, cardiovascular disease, cancer and premature mortality. It has been further hypothesized that nutritionally driven insulin exposure controls the rate of mammalian aging. Interventions that normalize/reduce plasma insulin concentrations might play a key role in the prevention and treatment of age-related decline, obesity, type 2 diabetes, cardiovascular disease and cancer. Caloric restriction, increasing hepatic insulin clearance and maximizing insulin sensitivity are at present the three main strategies available for managing hyperinsulinemia. This may slow down age-related physiological decline and prevent age-related diseases. Drugs that reduce insulin (hyper) secretion, normalize pulsatile insulin secretion and/or increase hepatic insulin clearance may also have the potential to prevent or delay the progression of hyperinsulinemia-mediated diseases. Future research should focus on new strategies to minimize hyperinsulinemia at an early stage, aiming at successfully preventing and treating hyperinsulinemia-mediated diseases.

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Telomere Length and Oxidative Stress and Its Relation with Metabolic Syndrome Components in the Aging

Biology ◽

10.3390/biology10040253 ◽

2021 ◽

Vol 10 (4) ◽

pp. 253

Author(s):

Graciela Gavia-García ◽

Juana Rosado-Pérez ◽

Taide Laurita Arista-Ugalde ◽

Itzen Aguiñiga-Sánchez ◽

Edelmiro Santiago-Osorio ◽

...

Keyword(s):

Oxidative Stress ◽

Metabolic Syndrome ◽

Telomere Length ◽

Scientific Evidence ◽

Telomeric Dna ◽

Biochemical Alterations ◽

The Metabolic Syndrome ◽

Age Related ◽

And Function

A great amount of scientific evidence supports that Oxidative Stress (OxS) can contribute to telomeric attrition and also plays an important role in the development of certain age-related diseases, among them the metabolic syndrome (MetS), which is characterised by clinical and biochemical alterations such as obesity, dyslipidaemia, arterial hypertension, hyperglycaemia, and insulin resistance, all of which are considered as risk factors for type 2 diabetes mellitus (T2DM) and cardiovascular diseases, which are associated in turn with an increase of OxS. In this sense, we review scientific evidence that supports the association between OxS with telomere length (TL) dynamics and the relationship with MetS components in aging. It was analysed whether each MetS component affects the telomere length separately or if they all affect it together. Likewise, this review provides a summary of the structure and function of telomeres and telomerase, the mechanisms of telomeric DNA repair, how telomere length may influence the fate of cells or be linked to inflammation and the development of age-related diseases, and finally, how the lifestyles can affect telomere length.

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