Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients.

Abstract

Deposition of amyloid in pancreatic islets is a common feature in human type 2 diabetic subjects but because of its insolubility and low tissue concentrations, the structure of its monomer has not been determined. We describe a peptide, of calculated molecular mass 3905 Da, that was a major protein component of amyloid-rich pancreatic extracts of three type 2 diabetic patients. After collagenase treatment, an extract containing 20-50% amyloid was solubilized by sonication into 70% formic acid and the peptide was purified by gel filtration followed by reverse-phase high-performance liquid chromatography. We term this peptide diabetes-associated peptide, as it was not detected in extracts of pancreas from any of six normal subjects. Diabetes-associated peptide contains 37 amino acids and is 46% identical to the sequences of rat and human calcitonin gene-related peptide, indicating that these peptides are related in evolution. Sequence identities with conserved residues of the insulin A chain were also seen in a 16-residue segment. On extraction, the islet amyloid is particulate and insoluble like the core particles of Alzheimer disease. Their monomers have similar molecular masses, each having a hydropathic region that can probably form 13-pleated sheets.

Ganglioside‐induced amyloid formation by human islet amyloid polypeptide in lipid rafts

“…Native human islet amyloid polypeptide (hIAPP) is the primary component of the amyloid deposits [6,7] found in the pancreatic islet of patients with type 2 DM [8,9]. The causal relationship between the formation of amyloid fibrils containing hIAPP and the onset of type 2 DM has not been resolved.…”

Calcitonin gene‐related peptide‐1 (CGRP‐1) is a potent regulator of glycogen metabolism in rat skeletal muscle

“…Noradrenaline has little effect on glycogen metabolism in skeletal muscle [9]. The neuropeptide calcitonin gene-related peptide (CGRP) has 46°70 primary amino acid sequence identity with the pancreatic peptide amylin [12]. Both peptides inhibit basal and insulinstimulated glycogen synthesis in incubated stripped soleus muscle preparations [10,13].…”

Is type 2 diabetes an amyloidosis and does it really matter (to patients)?

“…As they point out, it has long been known that many [8,[12][13][14] or perhaps most [15,16] type 2 diabetic patients are found to have islet amyloid deposits adjacent to their beta cells [17] when post mortem pancreatic tissue is examined histologically. Although islet amyloid has also been reported to occur in numbers of humans not known to have diabetes, the author of a major study cautioned that 'nondiabetic persons with hyaline islets may represent individuals with undiagnosed or potential diabetes' [18].…”

“…Islet amyloid, or hyaline as it was once known [12], has the beta cell hormone human amylin or human islet amyloid polypeptide (hIAPP) [17,19,20] as its monomer and arguably prompted the finding that first pin-pointed the islets as the likely location of diabetes causation [12]. Paradoxically, in marked contrast with amyloid-associated neurodegenerative diseases in neuropathology, this observation has so far received little recognition in the wider diabetes research field.…”