Effects of prolonged fasting and sustained lipolysis on insulin secretion and insulin sensitivity in normal subjects

Salgin, Burak; Marcovecchio, Maria Loredana; Humphreys, Sandy M.; Hill, Nathan R.; Chassin, Ludovic J.; Lunn, David J.; Hovorka, Roman; Dunger, David B.

doi:10.1152/ajpendo.90613.2008

Cited by 40 publications

(41 citation statements)

References 52 publications

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“…These metabolic effects of acipimox were shown previously in chronic (for weeks) treatment studies enrolling non-insulin-dependent diabetes mellitus (26), hyperlipoproteinemic patients (32), or subjects with both diseases (11). More recently, acipimox has also been investigated in acute (a few days) treatment studies in normal and diabetic subjects, confirming promising improvements in insulin sensitivity and NEFA levels (24,26). In general, chronic treatments with acipimox have been used at daily doses greater (ϳ1,200 mg) than those tested in short-term studies (250 -500 mg).…”

Section: Discussionsupporting

confidence: 57%

“…On the other hand, FFAs have been shown to potentially influence insulin-mediated functions by interfering with insulin receptor activation and downstream intracellular signaling pathways (20). The increase in plasma FFA levels might be mediated by both prolonged fasting (sustained lipolysis) and excessive fat intake (24). In the metabolic syndrome, the physiological FFA modifications are chronically exaggerated and might favor the final development of insulin resistance.…”

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confidence: 99%

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Acipimox reduces circulating levels of insulin and associated neutrophilic inflammation in metabolic syndrome

Montecucco¹,

Bertolotto

Vuilleumier

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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Metabolic syndrome is a proatherosclerotic condition clustering cardiovascular risk factors, including glucose and lipid profile alterations. The pathophysiological mechanisms favoring atherosclerotic inflammation in the metabolic syndrome remain elusive. Here, we investigated the potential role of the antilipolytic drug acipimox on neutrophil- and monocyte-mediated inflammation in the metabolic syndrome. Acipimox (500 mg) was orally administered to metabolic syndrome patients (n = 11) or healthy controls (n = 8). Serum and plasma was collected before acipimox administration (time 0) as well as 2-5 h afterward to assess metabolic and hematologic parameters. In vitro, the effects of the incubation with metabolic syndrome serum were assessed on human neutrophil and monocyte migration toward the proatherosclerotic chemokine CCL3. Two to five hours after acipimox administration, a significant reduction in circulating levels of insulin and nonesterified fatty acid (NEFA) was shown in metabolic syndrome patients. At time 0 and 2 h after acipimox administration, metabolic syndrome serum increased neutrophil migration to CCL3 compared with healthy controls. No effect was shown in human monocytes. At these time points, serum-induced neutrophil migration positively correlated with serum levels of insulin and NEFA. Metabolic syndrome serum or recombinant insulin did not upregulate CCR5 expression on neutrophil surface membrane, but it increased intracellular JNK1/2 phosphorylation. Insulin immunodepletion blocked serum-induced neutrophil migration and associated JNK1/2 phosphorylation. Although mRNA expression of acipimox receptor (GPR109) was shown in human neutrophils, 5-500 μM acipimox did not affect insulin-induced neutrophil migration. In conclusion, results suggest that acipimox inhibited neutrophil proatherosclerotic functions in the metabolic syndrome through the reduction in circulating levels of insulin

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Section: Discussionsupporting

confidence: 57%

mentioning

confidence: 99%

Acipimox reduces circulating levels of insulin and associated neutrophilic inflammation in metabolic syndrome

Montecucco¹,

Bertolotto

Vuilleumier

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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“…The relationship between portal insulin and GH sensitivity of the liver Human and other mammals are capable of prolonged fasting because they can recruit and utilize lipid stores when they exhaust readily available carbohydrates (20)(21)(22). Prolonged fasting is associated with a gradual decline in hepatic IGF1 production, which makes teleological sense due to the insulin-like effects of IGF1.…”

Section: Animal Studies Of the Actions Of Gh Versus Igf1mentioning

confidence: 99%

Hypothesis: Extra-hepatic acromegaly: a new paradigm?

Neggers

Kopchick

Jørgensen

et al. 2011

European Journal of Endocrinology

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Medical treatment of acromegaly with long-acting somatostatin analogs (LA-SMSA) and the GH receptor antagonist, pegvisomant (PEGV), has made it possible to achieve normal serum IGF1 concentrations in a majority of patients with acromegaly. These two compounds, however, impact the GH-IGF1 axis differently, which challenges the traditional biochemical assessment of the therapeutic response. We postulate that LA-SMSA in certain patients normalizes serum IGF1 levels in the presence of elevated GH actions in extra-hepatic tissues. This may result in persistent disease activity for which we propose the term extra-hepatic acromegaly. PEGV, on the other hand, blocks systemic GH actions, which are not necessarily reliably reflected by serum IGF1 levels, and this treatment causes a further elevation of serum GH levels. Medical treatment is therefore difficult to monitor with the traditional biomarkers. Moreover, the different modes of actions of LA-SMSA and PEGV make it attractive to use the two drugs in combination. We believe that it is time to challenge the existing concepts of treatment and monitoring of patients with acromegaly.

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“…To address whether insulin resistance is directly involved in reducing BAT activity and NST, a 48 to 60 h fasting period can be employed to induce insulin resistance in young, healthy individuals [17][18][19]. We have recently shown that this prolonged fasting leads to a 50% reduction in insulin sensitivity, as determined by the gold standard method, hyperinsulinaemic-euglycaemic clamp, probably due to increased NEFA levels and/or accumulation of triacylglycerols in peripheral tissues [18].…”

Section: Introductionmentioning

confidence: 99%

Glucose uptake in human brown adipose tissue is impaired upon fasting-induced insulin resistance

et al. 2014

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Aims/hypothesis Human brown adipose tissue (BAT) has recently emerged as a potential target in the treatment of type 2 diabetes, owing to its capacity to actively clear glucose from the circulation-at least upon cold exposure. The effects of insulin resistance on the capacity of human BAT to take up glucose are unknown. Prolonged fasting is known to induce insulin resistance in peripheral tissues in order to spare glucose for the brain. Methods We studied the effect of fasting-induced insulin resistance on the capacity of BAT to take up glucose during cold exposure as well as on cold-stimulated thermogenesis. BAT glucose uptake was assessed by means of cold-stimulated dynamic 2-deoxy-2-[ 18 F]fluoro-D-glucose positron emission tomography/computed tomography ([ 18 F]FDG-PET/CT) imaging.Results We show that a 54 h fasting period markedly decreases both cold-induced BAT glucose uptake and nonshivering thermogenesis (NST) during cold stimulation. In vivo molecular imaging and modelling revealed that the reduction of glucose uptake in BAT was due to impaired cellular glucose uptake and not due to decreased supply. Interestingly, decreased BAT glucose uptake upon fasting was related to a decrease in core temperature during cold exposure, pointing towards a role for BAT in maintaining normothermia in humans. Conclusions/interpretation Cold-stimulated glucose uptake in BAT is strongly reduced upon prolonged fasting. When cold-stimulated glucose uptake in BAT is also reduced under other insulin-resistant states, such as diabetes, cold-induced activation of BAT may not be a valid way to improve glucose clearance by BAT under such conditions. Trial registration: www.trialregister.nl NTR3523 Funding: This work was supported by the EU FP7 project DIABAT (HEALTH-F2-2011-278373

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Effects of prolonged fasting and sustained lipolysis on insulin secretion and insulin sensitivity in normal subjects

Abstract: Salgin B, Marcovecchio ML, Humphreys SM, Hill N, Chassin LJ, Lunn DJ, Hovorka R, Dunger DB. Effects of prolonged fasting and sustained lipolysis on insulin secretion and insulin sensitivity in normal subjects.

Cited by 40 publications

References 52 publications

Acipimox reduces circulating levels of insulin and associated neutrophilic inflammation in metabolic syndrome

Acipimox reduces circulating levels of insulin and associated neutrophilic inflammation in metabolic syndrome

Hypothesis: Extra-hepatic acromegaly: a new paradigm?

Glucose uptake in human brown adipose tissue is impaired upon fasting-induced insulin resistance

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