| 1. |
- Alvarsson, M, et al.
(författare)
-
Beneficial effects of insulin versus sulphonylurea on insulin secretion and metabolic control in recently diagnosed type 2 diabetic patients
- 2003
-
Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 26:8, s. 2231-2237
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE - To evaluate whether treatment with insulin in recently diagnosed type 2 diabetes is advantageous compared with glibenclamide treatment. RESEARCH DESIGN AND METHODS - ▀-Cell function, glycemic control, and quality of life were monitored over 2 years in 39 patients with islet cell antibody-negative type 2 diabetes diagnosed 0-2 years before inclusion in a Swedish multicenter randomized clinical trial. Patients were randomized to either two daily injections of premixed 30% soluble and 70% NPH insulin or glibenclamide (3.5-10.5 mg daily). C-peptide-glucagon tests were performed yearly in duplicate after 2-3 days of temporary withdrawal of treatment. RESULTS - After 1 year the glucagon-stimulated C-peptide response was increased in the insulin-treated group by 0.14 ▒ 0.08 nmol/l, whereas it was decreased by 0.12 ▒ 0.08 nmol/l in the glibenclamide group, P < 0.02 for difference between groups. After 2 years, fasting insulin levels were higher after treatment withdrawal in the insulin-treated versus the glibenclamide-treated group (P = 0.02). HbA1c levels decreased significantly during the first year in both groups, however, at the end of the second year, HbA1c had deteriorated in the glibenclamide group (P < 0.01), but not in the insulin-treated group. The difference in evolution of HbA1c during the second year was significant between groups, P < 0.02 A questionnaire indicated no difference in well-being related to treatment. CONCLUSIONS - Early insulin versus glibenclamide treatment in type 2 diabetes temporarily prolongs endogenous insulin secretion and promotes better metabolic control.
|
|
| 2. |
- Ankarcrona, M., et al.
(författare)
-
Current and future treatment of amyloid diseases
- 2016
-
Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 280:2, s. 177-202
-
Forskningsöversikt (refereegranskat)abstract
- There are more than 30 human proteins whose aggregation appears to cause degenerative maladies referred to as amyloid diseases or amyloidoses. These disorders are named after the characteristic cross--sheet amyloid fibrils that accumulate systemically or are localized to specific organs. In most cases, current treatment is limited to symptomatic approaches and thus disease-modifying therapies are needed. Alzheimer's disease is a neurodegenerative disorder with extracellular amyloid -peptide (A) fibrils and intracellular tau neurofibrillary tangles as pathological hallmarks. Numerous clinical trials have been conducted with passive and active immunotherapy, and small molecules to inhibit A formation and aggregation or to enhance A clearance; so far such clinical trials have been unsuccessful. Novel strategies are therefore required and here we will discuss the possibility of utilizing the chaperone BRICHOS to prevent A aggregation and toxicity. Type 2 diabetes mellitus is symptomatically treated with insulin. However, the underlying pathology is linked to the aggregation and progressive accumulation of islet amyloid polypeptide as fibrils and oligomers, which are cytotoxic. Several compounds have been shown to inhibit islet amyloid aggregation and cytotoxicity in vitro. Future animal studies and clinical trials have to be conducted to determine their efficacy in vivo. The transthyretin (TTR) amyloidoses are a group of systemic degenerative diseases compromising multiple organ systems, caused by TTR aggregation. Liver transplantation decreases the generation of misfolded TTR and improves the quality of life for a subgroup of this patient population. Compounds that stabilize the natively folded, nonamyloidogenic, tetrameric conformation of TTR have been developed and the drug tafamidis is available as a promising treatment. Read more articles from the symposium: Amyloid - a multifaceted player in human health and disease.
|
|
| 3. |
- Jurgens, Catherine A., et al.
(författare)
-
beta-Cell Loss and beta-Cell Apoptosis in Human Type 2 Diabetes Are Related to Islet Amyloid Deposition
- 2011
-
Ingår i: American Journal of Pathology. - : Elsevier BV. - 0002-9440 .- 1525-2191. ; 178:6, s. 2632-2640
-
Tidskriftsartikel (refereegranskat)abstract
- Amyloid deposition and reduced beta-cell mass are pathological hallmarks of the pancreatic islet in type 2 diabetes; however, whether the extent of amyloid deposition is associated with decreased beta-cell mass is debated. We investigated the possible relationship and, for the first time, determined whether increased islet amyloid and/or decreased beta-cell area quantified on histological sections is correlated with increased beta-cell apoptosis. Formalin-fixed, paraffin-embedded human pancreas sections from subjects with (n = 29) and without (n = 39) diabetes were obtained at autopsy (64 +/- 2 and 70 +/- 4 islets/subject, respectively). Amyloid and beta cells were visualized by thioflavin S and insulin inununolabeling. Apoptotic beta cells were detected by colabeling for insulin and by TUNEL. Diabetes was associated with increased amyloid deposition, decreased beta-cell area, and increased beta-cell apoptosis, as expected. There was a strong inverse correlation between beta-cell area and amyloid deposition (r = -0.42, P < 0.001). beta-Cell area was selectively reduced in individual amyloid-containing islets from diabetic subjects, compared with control subjects, but amyloid-free islets had beta-cell area equivalent to islets from control subjects. Increased amyloid 'deposition was associated with beta-cell apoptosis (r = 0.56, P < 0.01). Thus, islet amyloid is associated with decreased beta-cell area and increased beta-cell apoptosis, suggesting that islet amyloid deposition contributes to the decreased beta-cell mass that characterizes type 2 diabetes.
|
|
| 4. |
- Kollmer, Marius, et al.
(författare)
-
Electron tomography reveals the fibril structure and lipid interactions in amyloid deposits
- 2016
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 113:20, s. 5604-5609
-
Tidskriftsartikel (refereegranskat)abstract
- Electron tomography is an increasingly powerful method to study the detailed architecture of macromolecular complexes or cellular structures. Applied to amyloid deposits formed in a cell culture model of systemic amyloid A amyloidosis, we could determine the structural morphology of the fibrils directly in the deposit. The deposited fibrils are arranged in different networks, and depending on the relative fibril orientation, we can distinguish between fibril meshworks, fibril bundles, and amyloid stars. These networks are frequently infiltrated by vesicular lipid inclusions that may originate from the death of the amyloid-forming cells. Our data support the role of nonfibril components for constructing fibril deposits and provide structural views of different types of lipid-fibril interactions.
|
|
| 5. |
|
|
| 6. |
- Lundmark, Katarzyna, et al.
(författare)
-
Naturally occurring fibrillar proteins can induce AA amyloidosis by a prion-like mechanism
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Experimental AA amyloidosis, where the acute phase protein serum AA (SAA) forms amyloid fibrils, can be induced in mice provoked with inflannnatmy challenge. The time for development of amyloid is dramatically shortened when the animals concomitantly receive extract of a tissue from another mouse with amyloid 1-3. The active elusive principle has been named Amyloid Enhancing Factor (AEF) and experimental secondary amyloidosis was supposed to be a nucleation dependent process. The nature of the nucleus, however, was unknown for a long time. Our studies with synthetic amyloid-like fibrils made frmn short amyloidogenic pep tides instead of AEF 4, 5, indicate that the amyloid fibrils theruselves may act as nuclei for fibril formation (Fig. 1a). Here we present the enhanced development of AA -amyloidosis by naturally occurring amyloid-like protein fibrils.
|
|
| 7. |
|
|
| 8. |
- Lundmark, Katarzyna, et al.
(författare)
-
Transmissibility of systemic amyloidosis by a prion-like mechanism
- 2002
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 99:10, s. 6979-6984
-
Tidskriftsartikel (refereegranskat)abstract
- The generation of amyloid fibrils from an amyloidogenic polypeptide occurs by a nucleation-dependent process initiated in vitro by seeding the protein solution with preformed fibrils. This phenomenon is evidenced in vivo by the fact that amyloid protein A (AA) amyloidosis in mice is markedly accelerated when the animals are given, in addition to an inflammatory stimulus, an i.v. injection of protein extracted from AA amyloid-laden mouse tissue. Heretofore, the chemical nature of this “amyloid enhancing factor” (AEF) has not been definitively identified. Here we report that the active principle of AEF extracted from the spleen of mice with silver nitrate-induced AA amyloidosis was identified unequivocally as the AA fibril itself. Further, we demonstrated that this material was extremely potent, being active in doses <1 ng, and that it retained its biologic activity over a considerable length of time. Notably, the AEF was also effective when administered orally. Our studies have provided evidence that AA and perhaps other forms of amyloidosis are transmissible diseases, akin to the prion-associated disorders.
|
|
| 9. |
|
|
| 10. |
- Ma, Zhi, et al.
(författare)
-
Enhanced in vitro production of amyloid-like fibrils from mutant (S20G) islet amyloid polypeptide
- 2001
-
Ingår i: Amyloid. - : Informa UK Limited. - 1350-6129 .- 1744-2818. ; 8, s. 242-
-
Tidskriftsartikel (refereegranskat)abstract
- Islet amyloid polypeptide (IAPP, “amylin”) is the amyloid-fibril-forming polypeptide in the islets of Langerhans associated with type 2 diabetes mellitus. A missense mutation in the IAPP gene associated with early-onset type 2 diabetes has been identified in the Japanese population. This mutation results in a glycine for serine substitution at position 20 of the mature IAPP molecule. Whether or not formation of islet amyloid with resulting destruction of islet tissue is the cause of this diabetes is yet not known. The present in vitro study was performed in order to investigate any influence of the amino acid substitution on the fibril formation capacity. Synthetic full-length wild type (lAPPwt) and mutant (IAPPS20G) as well as corresponding truncated peptides (position 18-29) were dissolved in dimethylsulfoxide (DMSO) or in 10% acetic acid at a concentration of 10 mg/mL and their fibril forming capacity was checked by Congo red staining, electron microscopy, a Congo red affinity assay and Thioflavine T fluorometric assay. It was found that full-length and truncated IAPPS20G both formed more amyloid-like fibrils and did this faster compared to IAPPwt. The fibril morphology differed slightly between the preparations. Conclusion: The amino acid substitution (S20G) is situated close to the region of the IAPP molecule implicated in the IAPP fibrillogenesis. The significantly increased formation of amyloid-like fibrils by IAPPS20G is highly interesting and may be associated with an increased islet amyloid formation in vivo and of fundamental importance in the pathogenesis of this specific form of diabetes.
|
|
