Loss of entrainment of high-frequency plasma insulin oscillations in type 2 diabetes is likely a glucose-specific β-cell defect

Mao, Catherine S.; Berman, Nancy; Ipp, Eli

doi:10.1152/ajpendo.00555.2003

Cited by 7 publications

(9 citation statements)

References 37 publications

(43 reference statements)

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“…Similar responses were noted in 6-day unloaded rat soleus muscle [15] and additional studies showed that HS caused a decrease in insulin receptors in skeletal muscle [27] and activation of insulin-independent pathways mediating glucose uptake [28]. The changes in the insulin levels could be associated with plasma insulin oscillations noted as metabolic defects in Type-2 diabetes [29,30] or oscilllations of metabolism in the pancreas [31]. However, the decreased function of beta cells in response to HS in young animals in particular could also be due to an increase in oxidative stress.…”

Section: A D C Bsupporting

confidence: 64%

Pancreatic Response to Hind Limb Suspension in Rats is Affected by Age

Nichols¹,

Chowdhury²,

Dupont‐Versteegden³

2008

TOCCHEMJ

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Disuse and aging are associated with changes in glucose metabolism and insulin responsiveness of skeletal muscle. However, their combined effects on the islets of Langerhans in the pancreas and serum insulin levels have not been studied. The goal of this study was to investigate the response of the pancreas to disuse, induced by hind limb suspension (HS), in young and old animals. Male Fisher 344 X Brown Norway rats at 6 (young) and 32 (old) months of age were subjected to 14 days HS. Serum insulin and pancreas morphology were examined. Serum insulin concentration was lower in old rats, and decreased significantly following HS in young, but not old rats. Islets of Langerhans in the pancreas showed a more diffuse appearance in the old rats independent of HS, but no statistically significant differences were observed in islet area, cells per islet, or area occupied by islets. However, in old animals, but not young, HS was associated with an increase in islet number. No differences were observed in the percentage or area of insulin positive cells in the pancreas. We conclude that the insulin secretion response to disuse is lost at old age, and this can not be explained by changes in islet size or insulin positive cell number. The implications of changed appearance and number of islets in old rats in response to HS remain to be investigated.

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Section: A D C Bsupporting

confidence: 64%

Pancreatic Response to Hind Limb Suspension in Rats is Affected by Age

Nichols¹,

Chowdhury²,

Dupont‐Versteegden³

2008

TOCCHEMJ

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“…The ability of glucose to entrain endogenous insulin pulses is impaired in humans with type 2 diabetes (14,18) and in pancreatic islets from Zucker diabetic fatty (ZDF) rats (1). The loss of islet entrainment in diabetes has been suggested to be a glucose-specific manifestation of b-cell dysfunction (19). Periodic insulin signals may optimize the action of the hormone on target tissues (20)(21)(22), and as a result, impaired islet entrainment may contribute to the pathogenesis of diabetes.…”

Section: Introductionmentioning

confidence: 99%

Complex Patterns of Metabolic and Ca2+ Entrainment in Pancreatic Islets by Oscillatory Glucose

Pedersen

Mosekilde

Polonsky

et al. 2013

Biophysical Journal

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Glucose-stimulated insulin secretion is pulsatile and driven by intrinsic oscillations in metabolism, electrical activity, and Ca(2+) in pancreatic islets. Periodic variations in glucose can entrain islet Ca(2+) and insulin secretion, possibly promoting interislet synchronization. Here, we used fluorescence microscopy to demonstrate that glucose oscillations can induce distinct 1:1 and 1:2 entrainment of oscillations (one and two oscillations for each period of exogenous stimulus, respectively) in islet Ca(2+), NAD(P)H, and mitochondrial membrane potential. To our knowledge, this is the first demonstration of metabolic entrainment in islets, and we found that entrainment of metabolic oscillations requires voltage-gated Ca(2+) influx. We identified diverse patterns of 1:2 entrainment and showed that islet synchronization during entrainment involves adjustments of both oscillatory phase and period. All experimental findings could be recapitulated by our recently developed mathematical model, and simulations suggested that interislet variability in 1:2 entrainment patterns reflects differences in their glucose sensitivity. Finally, our simulations and recordings showed that a heterogeneous group of islets synchronized during 1:2 entrainment, resulting in a clear oscillatory response from the collective. In summary, we demonstrate that oscillatory glucose can induce complex modes of entrainment of metabolically driven oscillations in islets, and provide additional support for the notion that entrainment promotes interislet synchrony in the pancreas.

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“…In particular, modelling efforts have been focussed on the time dependent oscillatory behaviour of the insulin secretion, both of mitochondrial and electrical origin, which are lost in type two diabetes [22]–[24].…”

Section: Introductionmentioning

confidence: 99%

Mathematical Model of Metabolism and Electrophysiology of Amino Acid and Glucose Stimulated Insulin Secretion: In Vitro Validation Using a β-Cell Line

2013

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We integrated biological experimental data with mathematical modelling to gain insights into the role played by L-alanine in amino acid-stimulated insulin secretion (AASIS) and in D-glucose-stimulated insulin secretion (GSIS), details important to the understanding of complex β-cell metabolic coupling relationships. We present an ordinary differential equations (ODEs) based simplified kinetic model of core metabolic processes leading to ATP production (glycolysis, TCA cycle, L-alanine-specific reactions, respiratory chain, ATPase and proton leak) and Ca2+ handling (essential channels and pumps in the plasma membrane) in pancreatic β-cells and relate these to insulin secretion. Experimental work was performed using a clonal rat insulin-secreting cell line (BRIN-BD11) to measure the consumption or production of a range of important biochemical parameters (D-glucose, L-alanine, ATP, insulin secretion) and Ca2+ levels. These measurements were then used to validate the theoretical model and fine-tune the parameters. Mathematical modelling was used to predict L-lactate and L-glutamate concentrations following D-glucose and/or L-alanine challenge and Ca2+ levels upon stimulation with a non metabolizable L-alanine analogue. Experimental data and mathematical model simulations combined suggest that L-alanine produces a potent insulinotropic effect via both a stimulatory impact on β-cell metabolism and as a direct result of the membrane depolarization due to Ca2+ influx triggered by L-alanine/Na+ co-transport. Our simulations indicate that both high intracellular ATP and Ca2+ concentrations are required in order to develop full insulin secretory responses. The model confirmed that K+ ATP channel independent mechanisms of stimulation of intracellular Ca2+ levels, via generation of mitochondrial coupling messengers, are essential for promotion of the full and sustained insulin secretion response in β-cells.

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Loss of entrainment of high-frequency plasma insulin oscillations in type 2 diabetes is likely a glucose-specific β-cell defect

Cited by 7 publications

References 37 publications

Pancreatic Response to Hind Limb Suspension in Rats is Affected by Age

Pancreatic Response to Hind Limb Suspension in Rats is Affected by Age

Complex Patterns of Metabolic and Ca2+ Entrainment in Pancreatic Islets by Oscillatory Glucose

Mathematical Model of Metabolism and Electrophysiology of Amino Acid and Glucose Stimulated Insulin Secretion: In Vitro Validation Using a β-Cell Line

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