OBJECTIVES-We sought to 1) Determine whether solublemisfolded amylin or insoluble-fibrillar amylin may cause or result from diabetes in human amylin transgenic mice and 2) determine the role, if any, that insulin resistance might play in these processes.RESEARCH DESIGN AND METHODS-We characterized the phenotypes of independent transgenic mouse lines that display pancreas-specific expression of human amylin or a nonaggregating homolog, [ 25,28,29 Pro]human amylin, in an FVB/n background.RESULTS-Diabetes occurred in hemizygous human amylin transgenic mice from 6 weeks after birth. Glucose tolerance was impaired during the mid-and end-diabetic phases, in which progressive ␤-cell loss paralleled decreasing pancreatic and plasma insulin and amylin. Peripheral insulin resistance was absent because glucose uptake rates were equivalent in isolated soleus muscles from transgenic and control animals. Even in advanced diabetes, islets lacked amyloid deposits. In islets from nontransgenic mice, glucagon and somatostatin cells were present mainly at the periphery and insulin cells were mainly in the core; in contrast, all three cell types were distributed throughout the islet in transgenic animals.[ 25,28,29 Pro]human amylin transgenic mice developed neither ␤-cell degeneration nor glucose intolerance.CONCLUSIONS-Overexpression of fibrillogenic human amylin in these human amylin transgenic mice caused ␤-cell degeneration and diabetes through mechanisms independent from both peripheral insulin resistance and islet amyloid. These findings are consistent with ␤-cell death evoked by misfolded but soluble cytotoxic species, such as those formed by human amylin in vitro.

The aggregation of human amylin (hA) to form cytotoxic structures has been closely associated with the causation of type 2 diabetes. We sought to advance understanding of how altered expression and aggregation of hA might link β-cell degeneration with diabetes onset and progression, by comparing phenotypes between homozygous and hemizygous hA-transgenic mice. The homozygous mice displayed elevated islet hA that correlated positively with measures of oligomer formation (r=0.91; P<0.0001). They also developed hyperinsulinemia with transient insulin resistance during the prediabetes stage and then underwent rapid β-cell loss, culminating in severe juvenile-onset diabetes. The prediabetes stage was prolonged in the hemizygous mice, wherein β-cell dysfunction and extensive oligomer formation occurred in adulthood at a much later stage, when hA levels were lower (r=-0.60; P<0.0001). This is the first report to show that hA-evoked diabetes is associated with age, insulin resistance, progressive islet dysfunction, and β-cell apoptosis, which interact variably to cause the different diabetes syndromes. The various levels of hA elevation cause different extents of oligomer formation in the disease stages, thus eliciting early- or adult-onset diabetes syndromes, reminiscent of type 1 and 2 diabetes, respectively. Thus, the hA-evoked diabetes phenotypes differ substantively according to degree of amylin overproduction. These findings are relevant to the understanding of the pathogenesis and the development of experimental therapeutics for diabetes.