β-Cell Mitochondria and Insulin Secretion

Wollheim, Claes B.; Maechler, Pierre

doi:10.2337/diabetes.51.2007.s37

Cited by 107 publications

(99 citation statements)

References 87 publications

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“…Moreover, it is conceivable that modification of redox state regulates insulin secretion at the exocytosis level (16). Besides the role of ATP or ROS for islet insulin secretion, other amplifying signals are proposed (18,28,66). The putative involvement of regulatory messengers must be clarified, such as cAMP, that we previously highlighted for its involvement in the low insulin release in islets from LP fetuses (6).…”

Section: Discussionmentioning

confidence: 99%

Maternal low-protein diet alters pancreatic islet mitochondrial function in a sex-specific manner in the adult rat

Theys

Bouckenooghe

Ahn

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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Theys N, Bouckenooghe T, Ahn M-T, Remacle C, Reusens B. Maternal low-protein diet alters pancreatic islet mitochondrial function in a sex-specific manner in the adult rat. Am J Physiol Regul Integr Comp Physiol 297: R1516 -R1525, 2009. First published September 16, 2009; doi:10.1152/ajpregu.00280.2009.-Mitochondrial dysfunction may be a long-term consequence of a poor nutritional environment during early life. Our aim was to investigate whether a maternal low-protein (LP) diet may program mitochondrial dysfunction in islets of adult progeny before glucose intolerance ensues. To address this, pregnant Wistar rats were fed isocaloric diets containing either 20% protein (control) or 8% protein (LP diet) throughout gestation. From birth, offspring received the control diet. The mitochondrial function was analyzed in islets of 3-mo-old offspring. Related to their basal insulin release, cultured islets from both male and female LP offspring presented a lower response to glucose challenge and a blunted ATP production compared with control offspring. The expression of malate dehydrogenase as well as the subunit 6 of the ATP synthase encoded by mitochondrial genome (mtDNA) was lower in these islets, reducing the capacity of ATP production through the Krebs cycle and oxidative phosphorylation. However, mtDNA content was unchanged in LP islets compared with control. Several consequences of protein restriction during fetal life were more marked in male offspring. Only LP males showed an increased reactive oxygen species production associated with a higher expression of mitochondrial subunits of the electron transport chain NADH-ubiquinone oxireductase subunit 4L, an overexpression of peroxisome proliferator-activated receptor-␥ and uncoupling protein-2, and a strongly reduced beta-cell mass. In conclusion, mitochondrial function is clearly altered in islets from LP adult offspring in a sex-specific manner. That may provide a cellular explanation for the earlier development of glucose intolerance in male than in female offspring of dams fed an LP diet. developmental programming; malnutrition; metabolic syndrome; insulin secretion EPIDEMIOLOGICAL AND EXPERIMENTAL evidence shows a convincing relationship between a poor intrauterine nutritional environment and the subsequent development of metabolic disorders like insulin resistance, obesity, and cardiovascular disease in adulthood (11,12). The original concept of fetal programming of Type 2 diabetes mellitus (T2DM) was proposed by Hales et al. (12) who found in a cohort of adult men who had been smaller at birth that they were six times more prone to develop T2DM compared with individuals heavier at birth. These first epidemiological clues of programming have been largely replicated in many studies throughout the world (17, 27, 61). Currently, this concept is widely accepted, but the mechanistic basis is unclear.Recently, attention has focused on the involvement of mitochondria as putative targets linking physiological and molecular consequences of environmental disorders du...

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Section: Discussionmentioning

confidence: 99%

Maternal low-protein diet alters pancreatic islet mitochondrial function in a sex-specific manner in the adult rat

Theys

Bouckenooghe

Ahn

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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“…1). Thus, islets from HF mice appeared to be sensitised under K ATP -independent conditions, where metabolites from mitochondria, other than ATP, have been suggested to play an important role [16,17].…”

Section: Insulin Secretion In Vitromentioning

confidence: 99%

Enhanced mitochondrial metabolism may account for the adaptation to insulin resistance in islets from C57BL/6J mice fed a high-fat diet

et al. 2006

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Aim/hypothesis Hyperinsulinaemia maintains euglycaemia in insulin-resistant states. The precise cellular mechanisms by which the beta cells adapt are still unresolved. A peripherally derived cue, such as increased circulating fatty acids, may instruct the beta cell to initiate an adaptive programme to maintain glucose homeostasis. When this fails, type 2 diabetes ensues. Because mitochondria play a key role in beta cell pathophysiology, we tested the hypothesis that mitochondrial metabolism is critical for beta cell adaptation to insulin resistance. Methods C57BL/6J mice were given high-fat (HF) diet for 12 weeks. We then analysed islet hormone secretion, metabolism in vivo and in vitro, and beta cell morphology.Results HF diet resulted in insulin resistance and glucose intolerance but not frank diabetes. Basal insulin secretion was elevated in isolated islets from HF mice with almost no additional response provoked by high glucose. In contrast, a strong secretory response was seen when islets from HF mice were stimulated with fuels that require mitochondrial metabolism, such as glutamate, glutamine, alpha-ketoisocaproic acid and succinate. Moreover, while glucose oxidation was impaired in islets from HF mice, oxidation of glutamine and palmitate was enhanced. Ultrastructural analysis of islets in HF mice revealed an accumulation of lipid droplets in beta cells and a twofold increase in mitochondrial area. Conclusions/interpretation We propose that beta cells exposed to increased lipid flux in insulin resistance respond by increasing mitochondrial volume. This expansion is associated with enhanced mitochondrial metabolism as a means of beta cell compensation.

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“…Hence, an important axis exists between the nuclear and mitochondrial genomes in maintaining intracellular redox potential. Insulin biosynthetic and secretory capacities of pancreatic beta cells are highly dependent upon normal nuclear/mt communication [3], mt ATP generation [4], and exquisite sensitivity to ROS-mediated damage [5,6]. In this context, reports of mtDNA mutations associated with matrilineal type 2 diabetes (T2D) pedigrees in humans and rodents are becoming increasingly more frequent [7][8][9], accounting for up to 1% of human T2D.…”

Section: Introductionmentioning

confidence: 99%

mt-Nd2 Allele of the ALR/Lt mouse confers resistance against both chemically induced and autoimmune diabetes

et al. 2005

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Aims/hypothesis: ALR/Lt, a mouse strain with strong resistance to type 1 diabetes, is closely related to autoimmune type 1 diabetes-prone NOD/Lt mice. ALR pancreatic beta cells are resistant to the beta cell toxin alloxan, combinations of cytotoxic cytokines, and diabetogenic NOD T-cell lines. Reciprocal F1 hybrids between either ALR and NOD or ALR and NON/Lt, showed that alloxan resistance was transmitted to F1 progeny only when ALR was the maternal parent. Here we show that the mitochondrial genome (mtDNA) of ALR mice contributes resistance to diabetes. Methods: When F1 progeny from reciprocal outcrosses between ALR and NOD were backcrossed to NOD, a four-fold lower frequency of spontaneous type 1 diabetes development occurred when ALR contributed the mtDNA. Because of the apparent interaction between nuclear and mtDNA, the mitochondrial genomes were sequenced. Results: An ALR-specific sequence variation in the mt-Nd2 gene producing a leucine to methionine substitution at amino acid residue 276 in the NADH dehydrogenase 2 was discovered. An isoleucine to valine mutation in the mt-Co3 gene encoding COX3 distinguished ALR and NOD from NON and ALS. All four strains were distinguished by variation in a mt-encoded arginyl tRNA polyadenine tract. Shared alleles of mt-Co3 and mt-Tr comparing NOD and ALR allowed for exclusion of these two genes as candidates, implicating the mt-Nd2 variation as a potential ALR-derived type 1 diabetes protective gene. Conclusions/interpretation: The unusual resistance of ALR mice to both ROS-mediated and autoimmune type 1 diabete stresses reflects an interaction between the nuclear and mt genomes. The latter contribution is most likely via a single nucleotide polymorphism in mt-Nd2.

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β-Cell Mitochondria and Insulin Secretion

Cited by 107 publications

References 87 publications

Maternal low-protein diet alters pancreatic islet mitochondrial function in a sex-specific manner in the adult rat

Maternal low-protein diet alters pancreatic islet mitochondrial function in a sex-specific manner in the adult rat

Enhanced mitochondrial metabolism may account for the adaptation to insulin resistance in islets from C57BL/6J mice fed a high-fat diet

mt-Nd2 Allele of the ALR/Lt mouse confers resistance against both chemically induced and autoimmune diabetes

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