Uncoupling Protein-2 Negatively Regulates Insulin Secretion and Is a Major Link between Obesity, β Cell Dysfunction, and Type 2 Diabetes

Zhang, Chenyu; Baffy, György; Perret, Pascale; Krauß, Stefan; Peroni, Odile D.; Grujić, Danica; Hagen, Thilo; Vidal-Puig, António; Boss, Olivier; Kim, Young–Bum; Zheng, Xin Xiao; Wheeler, Michael B.; Shulman, Gerald I.; Chan, Catherine B.; Lowell, Bradford B.

doi:10.1016/s0092-8674(01)00378-6

Cited by 857 publications

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“…In humans, some, but not all (Klannemark et al 1998), studies showed that UCP2 gene variants are implicated in diabetes, obesity, and fat metabolism (Zhang et al 2001) and are strongly linked to resting energy expenditure (Astrup et al 1999;Buemann et al 2001;Walder et al 1998).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, both fast and caloric restriction increase the activity of UCP2 an inner mitochondrial membrane protein involved in the regulation of energy metabolism (Andrews 2010;Zhang et al 2001), mitochondrial biogenesis, fatty acid oxidation, substrate utilization and ROS elimination, providing neuroprotective and anti-aging effects (Conti et al 2006;Bechmann et al 2002).…”

Section: Introductionmentioning

confidence: 99%

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A/ASP/VAL allele combination of IGF1R, IRS2, and UCP2 genes is associated with better metabolic profile, preserved energy expenditure parameters, and low mortality rate in longevity

Barbieri

Boccardi

Esposito

et al. 2011

AGE

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A large array of gene involved in human longevity seems to be in relationship with insulin/ IGF1 pathway. However, if such genes interact each other, or with other genes, to reduce the age-related metabolic derangement and determine the long-lived phenotype has been poorly investigated. Thus, we tested the role of interchromosomal interactions among IGF1R, IRS2, and UCP2 genes on the probability to reach extreme old age in 722 unrelated Italian subjects (401 women and 321 men; mean age, 62.83±25.30 years) enrolled between 1998 and 1999. In particular, the G/A-IGF1R, Gly/Asp-IRS2, and Ala/ Val-UCP2 allele combination was tested for association with longevity, metabolic profile and energy expenditure parameters. The effect on all-cause and cause-specific mortality rate was also assessed after a mean follow-up of 6 years. The analysis revealed that AAV allele combination is associated with a decreased all-cause mortality risk (HR, 0.72; 95% CI, 0.63-0.91; p=0.03) and with a higher probability to reach the extreme of old age (OR, 3.185; 95% CI, 1.63-6.19; p=0.0006). The analysis also revealed lower HOMA-IR (Diff, −0.532, 95% CI, 0.886-0.17; p= 0.003), higher respiratory quotient (Diff, 0.0363, 95% CI, 0.014-0.05; p=0.001), and resting metabolic rate (Diff, 101.80693, 95% CI, p=0.038) for AAV allele combination. In conclusion, A-IGF1R/ Asp-IRS2/Val-UCP2 allele combination is associated with a decreased all-cause mortality risk and with an increased chance of longevity. Such an effect is probably due to the combined effect of IGF1R, IRS2, and UCP2 genes on energy metabolism and on the age-related metabolic remodeling capacity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A/ASP/VAL allele combination of IGF1R, IRS2, and UCP2 genes is associated with better metabolic profile, preserved energy expenditure parameters, and low mortality rate in longevity

Barbieri

Boccardi

Esposito

et al. 2011

AGE

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“…These mice have increased circulating insulin concentrations concomitant with reduced blood glucose in the fed state. Insulin secretion from glucose-stimulated isolated islets is also significantly enhanced and the ATP:ADP ratio is increased [111]. Conversely, overexpression of UCP2 in ZDF rat islets shows an increase in preproinsulin mRNA together with an improvement in GSIS [112].…”

Section: Fuel Metabolismmentioning

confidence: 96%

“…Rats fed a high fat diet for 3 weeks [109] and hyperlipidaemic, diabetic ob/ob mice [111] have increased islet UCP2 mRNA expression. Such lipid-associated upregulation could contribute to the development of insulin insufficiency and subsequent hyperglycaemia.…”

Section: Relation Of Ucp2 With Metabolic Diseasesmentioning

confidence: 99%

“…Since hyperglycaemia also induces UCP2 expression [117], it is possible that a feed-forward loop is generated which further exacerbates the insulin insufficiency, leading to the onset and progression of frank diabetes. Evidence for this hypothesis is provided by experiments showing that when ob/ob mice are crossed with UCP2 gene knockout mice, there is an improvement in glucose tolerance accompanied by increased insulin secretion [111].…”

Section: Relation Of Ucp2 With Metabolic Diseasesmentioning

confidence: 99%

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Uncoupling protein-2: evidence for its function as a metabolic regulator

2002

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Uncoupling protein-2 (UCP2) was discovered in 1997 but a definitive understanding of its functions has so far eluded investigators. Potential roles include regulating fat metabolism directly and indirectly via effects on insulin secretion. Also, UCP2 could also negatively modulate the production of reactive oxygen species (ROS). Although evidence in support of these functions is correlational, research on UCP2 mechanisms of action has recently been published. Studies of polymorphisms in the uncoupling protein-2 gene have not been included in detail here but are reviewed elsewhere [1,2]. For an in depth discussion of the uncoupling protein family of proteins, readers are referred to recent reviews [1, 3]. Chemical properties of uncoupling proteinsMitochondrial metabolism generates more than 90 % of the ATP required by organisms for routine cellular processes. The efficiency of ATP formation could be altered by demand, by drugs or by pathological processes. Uncoupling agents dissociate fuel oxidation in the electron transport chain of mitochondria from phosphorylation of substrate, namely ADP. Normally, glucose-derived NADH and FADH 2 stimulate Diabetologia (2002) AbstractUncoupling protein-2, discovered in 1997, belongs to a family of inner mitochondrial membrane proteins that, in general, function as carriers. The function(s) of uncoupling protein-2 have not yet been definitively described. However, mounting evidence suggests that uncoupling protein-2 could act in multiple tissues as a regulator of lipid metabolism. A role as a modulator of reactive oxygen species as a defence against infection is also postulated. In this review, a brief overview of the general and specific properties of uncoupling protein-2 is given and evidence for metabolic and immune regulatory functions is summarized.Uncoupling protein-2 could have particular importance in the regulation of lipid metabolism in adipose tissue and skeletal muscle. In addition, its ability to inhibit insulin secretion could also promote fat utilization over storage. Inhibition by uncoupling protein-2 of reactive oxygen species formation in macrophages and other tissues could have implications for regulation of immune function. The possibility of functions of uncoupling protein-2 in other tissues such as the brain are beginning to emerge. [Diabetologia (2002) 45: 174±187]

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Association of Fetal Catecholamines With Neonatal Hypoglycemia

Hoermann,

van Faassen,

Roeper

et al. 2024

JAMA Pediatr

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ImportancePerinatal stress and fetal growth restriction increase the risk of neonatal hypoglycemia. The underlying pathomechanism is poorly understood. In a sheep model, elevated catecholamine concentrations were found to suppress intrauterine insulin secretion, followed by hyperresponsive insulin secretion once the adrenergic stimulus subsided.ObjectiveTo determine whether neonates with risk factors for hypoglycemia have higher catecholamine concentrations in umbilical cord blood (UCB) and/or amniotic fluid (AF) and whether catecholamines are correlated with postnatal glycemia.Design, Setting, and ParticipantsIn a prospective cohort study of 328 neonates at a tertiary perinatal center from September 2020 through May 2022 in which AF and UCB were collected immediately during and after delivery, catecholamines and metanephrines were analyzed using liquid chromatography with tandem mass spectrometry. Participants received postnatal blood glucose (BG) screenings.ExposureRisk factor for neonatal hypoglycemia.Main Outcomes and MeasuresComparison of catecholamine and metanephrine concentrations between at-risk neonates and control participants, and correlation of concentrations of catecholamines and metanephrines with the number and severity of postnatal hypoglycemic episodes.ResultsIn this study of 328 neonates (234 in the risk group: median [IQR] gestational age, 270 [261-277] days; and 94 in the control group: median [IQR] gestational age, 273 [270-278] days), growth-restricted neonates showed increased UCB median (IQR) concentrations of norepinephrine (21.10 [9.15-42.33] vs 10.88 [5.78-18.03] nmol/L; P &lt; .001), metanephrine (0.37 [0.13-1.36] vs 0.12 [0.08-0.28] nmol/L; P &lt; .001), and 3-methoxytyramine (0.149 [0.098-0.208] vs 0.091 [0.063-0.149] nmol/L; P = .001). Neonates with perinatal stress had increased UCB median (IQR) concentrations of norepinephrine (22.55 [8.99-131.66] vs 10.88 [5.78-18.03] nmol/L; P = .001), normetanephrine (1.75 [1.16-4.93] vs 1.25 [0.86-2.56] nmol/L; P = .004), and 3-methoxytyramine (0.120 [0.085-0.228] vs 0.091 [0.063-0.149] nmol/L; P = .008) (P &lt; .0083 was considered statistically significant). Concentrations of UCB norepinephrine, metanephrine, and 3-methoxytyramine were negatively correlated with AF C-peptide concentration (rs = −0.212, P = .005; rs = −0.182, P = .016; and rs = −0.183, P = .016, respectively [P &lt; .017 was considered statistically significant]). Concentrations of UCB norepinephrine, metanephrine, and 3-methoxytyramine were positively correlated with the number of hypoglycemic episodes (BG concentration of 30-45 mg/dL) (rs = 0.146, P = .01; rs = 0.151, P = .009; and rs = 0.180, P = .002, respectively). Concentrations of UCB metanephrine and 3-methoxytyramine were negatively correlated with the lowest measured BG concentration (rs = −0.149, P = .01; and rs = −0.153, P = .008, respectively).Conclusions and RelevanceNeonates at risk for hypoglycemia displayed increased catecholamine and metanephrine concentrations that were correlated with postnatal hypoglycemic episodes and lower BG levels; these results are consistent with findings in a sheep model that fetal catecholamines are associated with neonatal β-cell physiology and that perinatal stress or growth restriction is associated with subsequent neonatal hyperinsulinemic hypoglycemia. Improving the pathomechanistic understanding of neonatal hypoglycemia may help to guide management of newborns at risk for hypoglycemia.

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Uncoupling Protein-2 Negatively Regulates Insulin Secretion and Is a Major Link between Obesity, β Cell Dysfunction, and Type 2 Diabetes

Cited by 857 publications

References 52 publications

A/ASP/VAL allele combination of IGF1R, IRS2, and UCP2 genes is associated with better metabolic profile, preserved energy expenditure parameters, and low mortality rate in longevity

A/ASP/VAL allele combination of IGF1R, IRS2, and UCP2 genes is associated with better metabolic profile, preserved energy expenditure parameters, and low mortality rate in longevity

Uncoupling protein-2: evidence for its function as a metabolic regulator

Association of Fetal Catecholamines With Neonatal Hypoglycemia

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