Noninsulin-Dependent Diabetes Mellitus as a Mitochondrial Genomic Disease

Mathews, Clayton E.; Berdanier, Carolyn D.

doi:10.3181/00379727-219-44321

Cited by 33 publications

(12 citation statements)

References 107 publications

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“…There is evidence that this population may provide critical support for neurons, and it is also possible that satellite cells retain their supportive role for neurons by proliferating when they are directly targeted. The axonal localization of PARP may reflect activation of mechanisms to repair damaged mitochondrial DNA, a postulated mechanism of cell death in diabetic neurons (24,43,44). Our antibody did not distinguish whether increased PARP in diabetes was from the parent molecule or cleaved product.…”

Section: Discussionmentioning

confidence: 82%

Sensory Neurons With Activated Caspase-3 Survive Long-Term Experimental Diabetes

Cheng

Zochodne²

2003

Diabetes

153

111

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Long-term experimental diabetes may best model the prominent and irreversible sensory deficits of chronic human diabetic polyneuropathy. Whereas irretrievable loss of sensory neurons, if present, would be an unfortunate feature of the disease, systematic unbiased counting has indicated that sensory neurons survive long-term experimental diabetes. In this study, we examined whether incipient cell loss from apoptosis in chronic experimental diabetes might nonetheless be in process, or whether neurons somehow adapt to their chronic insults. We examined sensory neurons in L4 and L5 dorsal root ganglia of long-term experimental streptozotocin-induced diabetic rats using transferase-mediated dUTP nick-end labeling (TUNEL), 4,6-diamidino-2-phenylindole (DAPI) staining of nuclear morphology, and electron microscopic appraisal of cell morphology. None provided any evidence for ongoing apoptosis. Despite this confirmation that sensory neurons survive, neurons had elevated expression of activated caspase-3 in unique patterns that included their nuclei, cytoplasm, and proximal axonal segments. Bcl-2 expression, a marker of antiapoptosis signaling, was observed in similar numbers of diabetic and nondiabetic neurons. In contrast, diabetic sensory neurons had elevated expression of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) in their nuclei, cytoplasm, and proximal axonal segments not overlapping with caspase-3 localization. Diabetic sensory neurons also had an apparent rise in cytoplasmic labeling of nitrotyrosine, a marker of peroxynitrite toxicity reported to activate PARP.

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Section: Discussionmentioning

confidence: 82%

Sensory Neurons With Activated Caspase-3 Survive Long-Term Experimental Diabetes

Cheng

Zochodne²

2003

Diabetes

153

111

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“…␤-Cell apoptotic death pathways can be activated by signals emanating from mitochondria in type 1 diabetes (64), and cumulative mutations in the mitochondrial genome can lead to increased ROS release accompanied by declining cellular energy production and insulin secretion as ␤-cells age (65). Thus, strategies that aim to preserve mitochondrial integrity and suppress intracellular generation of ROS should prove useful in preserving ␤-cell integrity and function (66,67). Data were collected from 24-week-old males maintained on an NIH-31 diet containing 4% fat.…”

Section: Discussionmentioning

confidence: 99%

Mouse Models and the Genetics of Diabetes

Leiter

Lee

2005

Diabetes

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In humans, both type 1 and type 2 diabetes exemplify genetically heterogeneous complex diseases in which epigenetic factors contribute to underlying genetic susceptibility. Extended human pedigrees often show inheritance of both diabetes types. A common pathophysiological denominator in both disease forms is pancreatic ␤-cell exposure to proinflammatory cytokines. Hence, it is intuitive that systemically expressed genes regulating ␤-cell ability to withstand chronic diabetogenic stress may represent a component of shared susceptibility to both major disease forms. In this review, the authors assemble evidence from genetic experiments using animal models developing clearly distinct diabetes syndromes to inquire whether some degree of overlap in genes contributing susceptibility can be demonstrated. The conclusion is that although overlap exists in the pathophysiological insults leading to ␤-cell destruction in the currently studied rodent models, the genetic bases seem quite distinct. Diabetes 54 (Suppl. 2):S151-S158, 2005 T he complex of genes in the HLA locus (IDDM1) contributing the major component of human susceptibility to autoimmune type 1 diabetes clearly provides a starting point for comparison for overlap with major susceptibility contributors to classic type 2 diabetes. Indications of humoral immunity against pancreatic ␤-cell autoantigens in 10 -30% of patients deemed clinically to have type 2 diabetes led to the concept that these patients exhibit latent autoimmune diabetes in adults (LADA), or "type 1.5" diabetes (1). Many LADA patients exhibit decreased frequency of the highest risk HLA class I and class II alleles and increased frequency of HLA alleles conferring strong protection against juvenile-onset type 1 diabetes (1). Although most type 2 diabetes cases clearly are not autoimmune in causation, and thus, specific HLA alleles are not identified as major type 2 diabetes susceptibility contributors, the LADA cases raise the possibility that a subset of non-HLA susceptibility may be shared. Under such circumstances, the absence of the high-risk HLA alleles results in a more slowly progressive disease that only presents in adulthood when pathophysiological stresses on ␤-cells, including obesity and insulin resistance shared in common with patients with classic type 2 diabetes, become prevalent.Polymorphisms in the upstream regulatory region of the insulin gene currently represent the strongest non-HLA locus linked to human type 1 diabetes susceptibility (IDDM2) (2). The pathogenic mechanism has not been associated with insulin processing, secretion, or action, but rather with the ability to express intrathymically and elicit T-cell tolerance to this major type 1 diabetes autoantigen (3,4). Alleles associated with resistance to type 1 diabetes, on the other hand, have been associated with polycystic ovarian syndrome (5), an insulin resistance syndrome that often leads to type 2 diabetes. Because type 2 diabetes often culminates in insulin deficiency attributed to ␤-cell failure associated with chron...

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“…Impaired mitochondrial function has been implicated in the promotion of apoptosis (7). Abnormalities in mitochondrial function have been reported in both type 1 and 2 diabetes (8,9). We hypothesized that apoptosis is involved in the pathogenesis of diabetic sensory neuropathy and that activation of the apoptosis cascade is associated with mitochondrial dysfunction.…”

Section: Diabetic Peripheral Neuropathy Evidence For Apoptosis and Asmentioning

confidence: 99%

Diabetic peripheral neuropathy: evidence for apoptosis and associated mitochondrial dysfunction.

2000

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We hypothesized that diabetic sensory neuropathy is associated with activation of apoptosis and concomitant mitochondrial dysfunction. Studies were performed in excised intact and acutely dissociated dorsal root ganglion (DRG) neurons from control and streptozotocininduced diabetic rats with decreased peripheral nerve conduction velocities (NCV). Apoptosis was increased in acutely dissociated DRG neurons from 3-to 6-weekold diabetic rats. Basal mitochondrial membrane potential (⌬) was significantly more positive in DRG neurons from diabetic rats. Depolarization with glutamate resulted in significantly more positive ⌬ and delayed recovery of ⌬ in neurons from diabetic rats. Restoration of euglycemia for 2 weeks with insulin implants normalized NCV, ⌬, and apoptosis. Intact and acutely dissociated neurons from diabetic rats demonstrated decreased Bcl-2 levels and translocation of cytochrome C from the mitochondria to the cytoplasm. Neither levels of Bax nor levels of Bcl-X L were altered in diabetic neuropathy. Apoptosis associated with mitochondrial dysfunction may contribute to the pathogenesis of diabetic sensory neuropathy.

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Noninsulin-Dependent Diabetes Mellitus as a Mitochondrial Genomic Disease

Cited by 33 publications

References 107 publications

Sensory Neurons With Activated Caspase-3 Survive Long-Term Experimental Diabetes

Sensory Neurons With Activated Caspase-3 Survive Long-Term Experimental Diabetes

Mouse Models and the Genetics of Diabetes

Diabetic peripheral neuropathy: evidence for apoptosis and associated mitochondrial dysfunction.

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