Abstract

Type 2 diabetes is a polygenic and genetically heterogeneous disease . The age of onset of the disease is usually late and environmental factors may be required to induce the complete diabetic phenotype. Susceptibility genes for diabetes have not yet been identified. Islet-brain-1 (IB1, encoded by MAPK8IP1), a novel DNA-binding transactivator of the glucose transporter GLUT2 (encoded by SLC2A2), is the homologue of the c-Jun amino-terminal kinase-interacting protein-1 (JIP-1; refs 2-5). We evaluated the role of IBi in beta-cells by expression of a MAPK8IP1 antisense RNA in a stable insulinoma beta-cell line. A 38% decrease in IB1 protein content resulted in a 49% and a 41% reduction in SLC2A2 and INS (encoding insulin) mRNA expression, respectively. In addition, we detected MAPK8IP1 transcripts and IBi protein in human pancreatic islets. These data establish MAPK8IP1 as a candidate gene for human diabetes. Sibpair analyses performed on i49 multiplex French families with type 2 diabetes excluded MAPK8IP1 as a major diabetogenic locus. We did, however, identify in one family a missense mutation located in the coding region of MAPK8IP1 (559N) that segregated with diabetes. In vitro, this mutation was associated with an inability of IB1 to prevent apoptosis induced by MAPK/ERK kinase kinase 1 (MEKK1) and a reduced ability to counteract the inhibitory action of the activated c-JUN amino-terminal kinase (JNK) pathway on INS transcriptional activity. Identification of this novel non-maturity onset diabetes of the young (MODY) form of diabetes demonstrates that IB1 is a key regulator of 3-cell function.

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Helbecque N, Abderrahamani A, Meylan L, Riederer B, Mooser V, Miklossy J, Delplanque J, Boutin P, Nicod P, Haefliger JA, Cottel D, Amouyel P, Froguel P, Waeber G. .Islet-brain1/C-Jun N-terminal kinase interacting protein-1 (IB1/JIP-1) promoter variant is associated with Alzheimer's disease. Mol Psychiatry. 2003 Apr;8(4):413-22, 363

Erratum inMol Psychiatry. 2003 Nov;8(11):947. Abderrhamani A [corrected to Abderrahamani A].

Abstract

Islet-brain1 (IB1) or c-Jun NH2 terminal kinase interacting protein-1 (JIP-1), the product of the MAPK8IP1 gene, functions as a neuronal scaffold protein to allow signalling specificity. IB1/JIP-1 interacts with many cellular components including the reelin receptor ApoER2, the low-density lipoprotein receptor-related protein (LRP), kinesin and the Alzheimer's amyloid precursor protein. Coexpression of IB1/JIP-1 with other components of the c-Jun NH2 terminal-kinase (JNK) pathway activates the JNK activity; conversely, selective disruption of IB1/JIP-1 in mice reduces the stress-induced apoptosis of neuronal cells. We therefore hypothesized that IB1/JIP-1 is a risk factor for Alzheimer's disease (AD). By immunocytochemistry, we first colocalized the presence of IB1/JIP-1 with JNK and phosphorylated tau in neurofibrillary tangles. We next identified a -499A>G polymorphism in the 5' regulatory region of the MAPK8IP1 gene. In two separate French populations the -499A>G polymorphism of MAPK8IP1 was not associated with an increased risk to AD. However, when stratified on the +766C>T polymorphism of exon 3 of the LRP gene, the IB1/JIP-1 polymorphism was strongly associated with AD in subjects bearing the CC genotype in the LRP gene. The functional consequences of the -499A>G polymorphism of MAPK8IP1 was investigated in vitro. In neuronal cells, the G allele increased transcriptional activity and was associated with an enhanced binding activity. Taken together, these data indicate that the increased transcriptional activity in the presence of the G allele of MAPK8IP1 is a risk factor to the onset of in patients bearing the CC genotype of the LRP gene.

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The role of chronic inflammation and chronic infection in type 2 diabetes

Various types of spirochetes (oral, intestinal and other types of spirochetes may all contrinute), Chlamydia pneumoniae, Helicobacter pylori and other. yet not characteriued bacteria were detected at the site of islet lesions in addition to components of local chronic inflammation.

Judith Miklossy, Ralph Martins, Nune Darbinian, Kamel Khalili and Patrick L. McGeer. Type 2 Diabetes: Local Inflammation and Direct Effect of Bacterial Toxic Components. The Open Pathology Journal, 2008, 2, 86-95

http://www.benthamscience.com/open/topatj/articles/V002/86TOPATJ.pdf

Abstract:

Objectives: It has been known for almost a century that amyloidosis is frequently associated with chronic bacterial infection. Islet amyloid deposit is characteristic of type 2 diabetes. Periodontal disease, which is predominantly caused by several Gram negative bacteria, is a risk factor for type 2 diabetes. The goal of the study was to explore whether bacteria or their toxic components may play a role in type 2 diabetes.

Material & Methods: The pancreas in 22 autopsy cases was analyzed for the presence of lipopolysaccharide (LPS), bacterial peptidoglycan (BPG) and local inflammatory processes. Ten of the cases had clinically diagnosed type 2 diabetes, and 12 were age matched controls.

Results:The results of an immunohistochemical analysis showed the presence of LPS and BPG in association with islet amyloid deposits in all the 10 diabetic cases as well as in 3 controls with clinically silent amyloid deposits. pneumoniae Clumps of HLA-DR positive activated macrophages, abundant immunoreactivity to the activated complement components C3d, C4d and C5b-9, the terminal attack complex, and a mild numbers of T4 and particularly of T8 lymphocytes
were present in the pancreas of all diabetic cases.Chlamydiaand Helicobacter pylori specific antigens were detected in the affected islets in a subset of diabetic patients.

Conclusions:These results suggest that bacteria or their slowly degradable remnants may initiate and sustain chronic inflammation in the pancreas and therefore play a role in the pathogenesis of type 2 diabetes. They also indicate that local immune responses, including activation of the classical complement pathway are important in the pathogenesis of type 2 diabetes. There may also be some involvement of the adaptive immune system. Further investigations are essential since a parallel use of antibacterial and anti-inflammatory drugs may prevent or slow down the disease progression.

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As we have previously observed beta amyloid and pathologically phosphorylated tau inclusions showing immunohistochemical and ultrastructural properties of tangles and curly fibers in other organs than the brain here we show that they are also present in the affected islets in type 2 diabètes. Other similarities between Alzheimer's disease and type 2 diabetes include the involvement of chronic inflammation and chronic infection in their pathogenesis, highlighted in the previous two papers.

Miklossy J, Qing H, Radenovic A, Kis A, Vileno B, Làszló F, Miller L, Martins RN, Waeber G, Mooser V, Bosman F, Khalili K, Darbinian N, McGeer PL. Beta amyloid and hyperphosphorylated tau deposits in the pancreas in type 2 diabetes.Neurobiol Aging. 2010 Sep;31(9):1503-15. doi: 10.1016/j.neurobiolaging.2008.08.019. Epub 2008 Oct 23.

Abstract

Strong epidemiologic evidence suggests an association between Alzheimer disease (AD) and type 2 diabetes. To determine if amyloid beta (Abeta) and hyperphosphorylated tau occurs in type 2 diabetes, pancreas tissues from 21 autopsy cases (10 type 2 diabetes and 11 controls) were analyzed. APP and tau mRNAs were identified in human pancreas and in cultured insulinoma beta cells (INS-1) by RT-PCR. Prominent APP and tau bands were detected by Western blotting in pancreatic extracts. Aggregated Abeta, hyperphosphorylated tau, ubiquitin, apolipoprotein E, apolipoprotein(a), IB1/JIP-1 and JNK1 were detected in Langerhans islets in type 2 diabetic patients. Abeta was co-localized with amylin in islet amyloid deposits. In situ beta sheet formation of islet amyloid deposits was shown by infrared microspectroscopy (SIRMS). LPS increased APP in non-neuronal cells as well. We conclude that Abeta deposits and hyperphosphorylated tau are also associated with type 2 diabetes, highlighting common pathogenetic features in neurodegenerative disorders, including AD and type 2 diabetes and suggesting that Abeta deposits and hyperphosphorylated tau may also occur in other organs than the brain.

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Mooser V, Helbecque N, Miklossy J, Marcovina SM, Nicod P, Amouyel P. Interactions between apolipoprotein E and apolipoprotein(a) in patients with late-onset Alzheimer disease.Ann Intern Med. 2000 Apr 4;132(7):533-7

Abstract

BACKGROUND: Apolipoprotein(a) [apo(a)], the distinctive, highly polymorphic glycoprotein of lipoprotein(a), shares a series of common features with apolipoprotein E (apoE), which is implicated in the development of Alzheimer disease.

OBJECTIVE: To determine whether apo(a) is associated with Alzheimer disease.

DESIGN: Case-control study.

SETTING: University hospitals in Europe.

PARTICIPANTS: 285 patients with Alzheimer disease and 296 controls.

MEASUREMENTS: Plasma lipoprotein(a) levels, size of the apo(a) isoforms, and apoE and apo(a) genotyping.

RESULTS: Among carriers of the apoE epsilon4 allele, lipoprotein(a) was associated with a progressive, age-dependent increased risk for late-onset Alzheimer disease (odds ratio for patients >80 years of age, 6.0 [95% CI, 1.2 to 30.8]; P<0.01). Among noncarriers older than 80 years of age, lipoprotein(a) was associated with a reduced risk for Alzheimer disease (odds ratio, 0.4 [CI, 0.2 to 0.91; P<0.05).

CONCLUSIONS: In this convenience sample, lipoprotein(a) was an additional risk factor for late-onset Alzheimer disease in carriers of the apoE epsilon4 allele. However, lipoprotein(a) may protect against late-onset Alzheimer disease in noncarriers.

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