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Spontaneous diabetes in hemizygous human amylin transgenic mice that developed neither islet amyloid nor peripheral insulin resistance.

Wong WP, Scott DW, Chuang CL, Zhang S, Liu H, Ferreira A, Saafi EL, Choong YS, Cooper GJ - Diabetes (2008)

Bottom Line: Glucose tolerance was impaired during the mid- and end-diabetic phases, in which progressive beta-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.These findings are consistent with beta-cell death evoked by misfolded but soluble cytotoxic species, such as those formed by human amylin in vitro.

View Article: PubMed Central - PubMed

Affiliation: School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand.

ABSTRACT

Objectives: We sought to 1) Determine whether soluble-misfolded 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 beta-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 beta-cell degeneration nor glucose intolerance.

Conclusions: Overexpression of fibrillogenic human amylin in these human amylin transgenic mice caused beta-cell degeneration and diabetes through mechanisms independent from both peripheral insulin resistance and islet amyloid. These findings are consistent with beta-cell death evoked by misfolded but soluble cytotoxic species, such as those formed by human amylin in vitro.

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Glucose tolerance, insulin tolerance, and muscle glucose uptake during diabetes progression in human amylin transgenic mice. A: IPGTT in human amylin transgenic (○, n = 18), [25,28,29Pro]human amylin transgenic (□, n = 4), and nontransgenic control (•, n = 16) mice. B: IPITT in human amylin transgenic (○, n = 15) and nontransgenic littermates (•, n = 14). C: In vitro glucose uptake in soleus muscles incubated without (basal) and with 2 mU/ml insulin in fasted human amylin transgenic (▪, n = 7) and nontransgenic controls (□, n = 7). *P < 0.05, **P < 0.01, and ***P < 0.001.
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f2: Glucose tolerance, insulin tolerance, and muscle glucose uptake during diabetes progression in human amylin transgenic mice. A: IPGTT in human amylin transgenic (○, n = 18), [25,28,29Pro]human amylin transgenic (□, n = 4), and nontransgenic control (•, n = 16) mice. B: IPITT in human amylin transgenic (○, n = 15) and nontransgenic littermates (•, n = 14). C: In vitro glucose uptake in soleus muscles incubated without (basal) and with 2 mU/ml insulin in fasted human amylin transgenic (▪, n = 7) and nontransgenic controls (□, n = 7). *P < 0.05, **P < 0.01, and ***P < 0.001.

Mentions: Hemizygous human amylin transgenic mice developed hyperglycemia from 6 weeks after birth (Fig. 1A), from which time blood glucose values were elevated compared with controls (P < 0.01). Blood glucose remained significantly elevated throughout the entire 31-week monitoring period (Fig. 1A). Ninety-six percent of the transgenic mice developed diabetes during this monitoring period, with a mean onset time of 11.2 weeks (Fig. 1B). Intraperitoneal GTTs (IPGTTs) performed in fasted animals at the mid-diabetic stage (Fig. 2A) demonstrated impaired glucose tolerance and elevated fasting blood glucose (Fig. 2A) in human amylin transgenic mice (P < 0.05). The lack of glucose-stimulated insulin secretion during GTT present in human amylin transgenic mice (t0 29.9 ± 15.1 cf. t15 39.1 ± 18.5 pmol/l; NS), is consistent with impaired β-cell function. In contrast, we detected a positive insulin response to glucose in the control nontransgenic mice (t0 26.2 ± 4.3 cf. t15 128.6 ± 55.7 pmol/l; P < 0.05). Neither fasting hyperglycemia nor impaired glucose tolerance was present in [25,28,29Pro]human amylin transgenic mice (Fig. 2A), wherein blood glucose concentrations remained equivalent to control levels at all times during the observation period (from birth to 24 weeks of age) (Fig. 1A).


Spontaneous diabetes in hemizygous human amylin transgenic mice that developed neither islet amyloid nor peripheral insulin resistance.

Wong WP, Scott DW, Chuang CL, Zhang S, Liu H, Ferreira A, Saafi EL, Choong YS, Cooper GJ - Diabetes (2008)

Glucose tolerance, insulin tolerance, and muscle glucose uptake during diabetes progression in human amylin transgenic mice. A: IPGTT in human amylin transgenic (○, n = 18), [25,28,29Pro]human amylin transgenic (□, n = 4), and nontransgenic control (•, n = 16) mice. B: IPITT in human amylin transgenic (○, n = 15) and nontransgenic littermates (•, n = 14). C: In vitro glucose uptake in soleus muscles incubated without (basal) and with 2 mU/ml insulin in fasted human amylin transgenic (▪, n = 7) and nontransgenic controls (□, n = 7). *P < 0.05, **P < 0.01, and ***P < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2551684&req=5

f2: Glucose tolerance, insulin tolerance, and muscle glucose uptake during diabetes progression in human amylin transgenic mice. A: IPGTT in human amylin transgenic (○, n = 18), [25,28,29Pro]human amylin transgenic (□, n = 4), and nontransgenic control (•, n = 16) mice. B: IPITT in human amylin transgenic (○, n = 15) and nontransgenic littermates (•, n = 14). C: In vitro glucose uptake in soleus muscles incubated without (basal) and with 2 mU/ml insulin in fasted human amylin transgenic (▪, n = 7) and nontransgenic controls (□, n = 7). *P < 0.05, **P < 0.01, and ***P < 0.001.
Mentions: Hemizygous human amylin transgenic mice developed hyperglycemia from 6 weeks after birth (Fig. 1A), from which time blood glucose values were elevated compared with controls (P < 0.01). Blood glucose remained significantly elevated throughout the entire 31-week monitoring period (Fig. 1A). Ninety-six percent of the transgenic mice developed diabetes during this monitoring period, with a mean onset time of 11.2 weeks (Fig. 1B). Intraperitoneal GTTs (IPGTTs) performed in fasted animals at the mid-diabetic stage (Fig. 2A) demonstrated impaired glucose tolerance and elevated fasting blood glucose (Fig. 2A) in human amylin transgenic mice (P < 0.05). The lack of glucose-stimulated insulin secretion during GTT present in human amylin transgenic mice (t0 29.9 ± 15.1 cf. t15 39.1 ± 18.5 pmol/l; NS), is consistent with impaired β-cell function. In contrast, we detected a positive insulin response to glucose in the control nontransgenic mice (t0 26.2 ± 4.3 cf. t15 128.6 ± 55.7 pmol/l; P < 0.05). Neither fasting hyperglycemia nor impaired glucose tolerance was present in [25,28,29Pro]human amylin transgenic mice (Fig. 2A), wherein blood glucose concentrations remained equivalent to control levels at all times during the observation period (from birth to 24 weeks of age) (Fig. 1A).

Bottom Line: Glucose tolerance was impaired during the mid- and end-diabetic phases, in which progressive beta-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.These findings are consistent with beta-cell death evoked by misfolded but soluble cytotoxic species, such as those formed by human amylin in vitro.

View Article: PubMed Central - PubMed

Affiliation: School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand.

ABSTRACT

Objectives: We sought to 1) Determine whether soluble-misfolded 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 beta-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 beta-cell degeneration nor glucose intolerance.

Conclusions: Overexpression of fibrillogenic human amylin in these human amylin transgenic mice caused beta-cell degeneration and diabetes through mechanisms independent from both peripheral insulin resistance and islet amyloid. These findings are consistent with beta-cell death evoked by misfolded but soluble cytotoxic species, such as those formed by human amylin in vitro.

Show MeSH
Related in: MedlinePlus