β-Amyloid-induced cognitive dysfunction impairs glucose homeostasis by increasing insulin resistance and decreasing β-cell mass in non-diabetic and diabetic rats.
OBJECTIVE
β-Amyloid accumulation in the brain may impair glucose homeostasis in both the brain and peripheral tissues. The present study investigated whether β-amyloid deposition in the hippocampus impairs glucose homeostasis by altering insulin sensitivity, glucose-stimulated insulin secretion or β-cell mass.


METHODS
Male rats were divided into two groups: a non-diabetic sham group and a diabetic partial pancreatectomized (Px) group. Each group was then subdivided into three treatment groups that received intra-CA1 infusions of β-amyloid (25-35; AMY), β-amyloid (35-25; RAMY; non-plaque forming), or saline at a rate of 3.6 nmol/day for 14 days.


RESULTS
After 4weeks, cognitive function measured by passive avoidance and water maze tests was impaired in non-diabetic rats that received AMY compared with rats that received saline or RAMY. Furthermore, diabetes exacerbated cognitive dysfunction in AMY-infused rats. This was associated with the hyperphosphorylation of tau as a result of attenuated insulin signaling (pAkt→pGSK) through decreased phosphorylation of cAMP responding element binding protein in the hippocampus of non-diabetic and diabetic rats. AMY exacerbated whole-body and hepatic insulin resistance in non-diabetic and diabetic rats. However, AMY potentiated glucose-stimulated insulin secretion in non-diabetic and diabetic rats, but caused decreased β-cell mass via increased β-cell apoptosis and decreased β-cell proliferation. As a result, glucose homeostasis was maintained by potentiating insulin secretion in diabetic rats, but may not be sustainable with further decreases in β-cell mass.


CONCLUSIONS
Cognitive dysfunction attributable to β-amyloid accumulation in the hippocampus might be related to disturbed glucose homeostasis due to increased insulin resistance and decreased β-cell mass.
Food and Nutrition, Obesity/Diabetes Research Center, Hoseo University, Asan, Korea. Electronic address: smpark@hoseo.edu.
Sunmin
S
Park
Da Sol
DS
Kim
Suna
S
Kang
Na Rang
NR
Moon
D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D003071:Cognition / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D015309:Glucose Clamp Technique; D006624:Hippocampus / Q000187:drug effects; D006706:Homeostasis / Q000502:physiology*; D007150:Immunohistochemistry; D007267:Injections; D007333:Insulin Resistance / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D010179:Pancreas / Q000473:pathology; D010180:Pancreatectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
D016229:Amyloid beta-Peptides; D005947:Glucose
5-bromo-2-deoxyuridine; AMY; BrdU; CREB; Cognitive dysfunction; GSK; HOMA-IR; Homeostatic model assessment for insulin resistance.; Insulin resistance; Insulin secretion; PKB or Akt; Px; RAMY; Sham; cAMP responding element binding protein; glycogen synthase kinase; partial pancreatectomy; protein kinase B; sham-operation; β-amyloid; β-amyloid (25–35); β-amyloid (35–25); β-cell apoptosis