Folate and vitamin B-12 deficiencies additively impaire memory function and disturb the gut microbiota in amyloid-ß infused rats.

Folate and vitamin B12(V-B12) deficiencies are associated with metabolic diseases that may impair memory function. We hypothesized that folate and V-B12 may differently alter mild cognitive impairment, glucose metabolism, and inflammation by modulating the gut microbiome in rats with Alzheimer's disease (AD)-like dementia. The hypothesis was examined in hippocampal amyloid-ß infused rats, and its mechanism was explored. Rats that received an amyloid-ß(25-35) infusion into the CA1 region of the hippocampus were fed either control(2.5 mg folate plus 25 µg V-B12/kg diet; AD-CON, n = 10), no folate(0 folate plus 25 µg V-B12/kg diet; AD-FA, n = 10), no V-B12(2.5 mg folate plus 0 µg V-B12/kg diet; AD-V-B12, n = 10), or no folate plus no V-B12(0 mg folate plus 0 µg V-B12/kg diet; AD-FAB12, n = 10) in high-fat diets for 8 weeks. AD-FA and AD-VB12 exacerbated bone mineral loss in the lumbar spine and femur whereas AD-FA lowered lean body mass in the hip compared to AD-CON(P < 0.05). Only AD-FAB12 exacerbated memory impairment by 1.3 and 1.4 folds, respectively, as measured by passive avoidance and water maze tests, compared to AD-CON(P < 0.01). Hippocampal insulin signaling and neuroinflammation were attenuated in AD-CON compared to Non-AD-CON. AD-FAB12 impaired the signaling (pAkt→pGSK-3ß) and serum TNF-α and IL-1ß levels the most among all groups. AD-CON decreased glucose tolerance by increasing insulin resistance compared to Non-AD-CON. AD-VB12 and AD-FAB12 increased insulin resistance by 1.2 and 1.3 folds, respectively, compared to the AD-CON. AD-CON and Non-AD-CON had a separate communities of gut microbiota. The relative counts of Bacteroidia were lower and those of Clostridia were higher in AD-CON than Non-AD-CON. AD-FA, but not V-B12, separated the gut microbiome community compared to AD-CON and AD-VB12(P = 0.009). In conclusion, folate and B-12 deficiencies impaired memory function by impairing hippocampal insulin signaling and gut microbiota in AD rats.

Fermented soybeans, Chungkookjang, prevent hippocampal cell death and ß-cell apoptosis by decreasing pro-inflammatory cytokines in gerbils with transient artery occlusion.

Since Chungkookjang, a short-term fermented soybean, is known to improve glucose metabolism and antioxidant activity, it may prevent the neurological symptoms and glucose disturbance induced by artery occlusion. We investigated the protective effects and mechanisms of traditional (TFC) and standardized Chungkookjang fermented with Bacillus licheniformis (BLFC) against ischemia/reperfusion damage in the hippocampal CA1 region and against hyperglycemia after transient cerebral ischemia in gerbils. Gerbils were subjected to either an occlusion of the bilateral common carotid arteries for 8 min to render them ischemic or a sham operation. Ischemic gerbils were fed either a 40% fat diet containing 10% of either cooked soybean (CSB), TFC, or BLFC for 28 days. Neuronal cell death and cytokine expression in the hippocampus, neurological deficit, serum cytokine levels, and glucose metabolism were measured. TFC and BLFC contained more isoflavonoid aglycones than CSB. Artery occlusion increased the expressions of IL-1ß and TNF-α as well as cell death in the hippocampal CA1 region and induced severe neurological symptoms. CSB, TFC, and BLFC prevented the neuronal cell death and the symptoms such as dropped eyelid, bristling hair, reduced muscle tone and flexor reflex, and abnormal posture and walking patterns, and suppressed cytokine expressions. CSB was less effective than TFC and BLFC. Artery occlusion induced glucose intolerance due to decreased insulin secretion and ß-cell mass. TFC and BLFC prevented the impairment of glucose metabolism by artery occlusion. Especially TFC and BLFC increased ß-cell proliferation and suppressed the ß-cell apoptosis by suppressing TNF-α and IL-1ß which in turn decreased cleaved caspase-3 that caused apoptosis. In conclusion, TFC and BLFC may prevent and alleviate neuronal cell death in the hippocampal CA1 region and neurological symptoms and poststroke hyperglycemia in gerbils with artery occlusion. This might be associated with increased isoflavonoid aglycones.

Exercise training attenuates cerebral ischemic hyperglycemia by improving hepatic insulin signaling and ß-cell survival.

AIMS: Preventing hyperglycemia after acute stroke attenuates complications of cerebral ischemia and reduces the risk of mortality. We investigated whether regular exercise prevents neuronal cell death and post-stroke hyperglycemia in gerbils after cerebral ischemia. MAIN METHODS: Cerebral ischemia was induced by carotid artery occlusion for 8min. The gerbils that underwent ischemic or sham operations were randomly subdivided into exercise (ran on inclined treadmill at 20m/min for 30min 5days per week for 1week prior to surgery) or non-exercise groups. Gerbils were fed a 40% fat diet and after 28days, glucose metabolism, serum cytokine levels and cognitive function was measured. KEY FINDINGS: Artery occlusion resulted in a 64% reduction in hippocampal CA1 neurons in comparison to the sham gerbils, and caused decreased neuronal mass and impaired cognitive function. Exercise partially prevented neuronal death and improved ischemia-induced glucose intolerance. Ischemia decreased hepatic insulin signaling and exacerbated insulin resistance whereas exercise prevented the disturbance. Insulin secretion was lower in ischemic gerbils than sham gerbils, due to lowered pancreatic ß-cell mass caused by increased ß-cell apoptosis and decreased ß-cell proliferation, which were also prevented by exercise. Increase of apoptosis was associated with elevated caspase-3 activity, consistent with increased serum tumor necrosis factor (TNF)-α and interleukin (IL)-1ß levels. SIGNIFICANCE: Hippocampal neuronal cell death induces hyperglycemia due to attenuated hepatic insulin signaling and decreased ß-cell mass by increased ß-cell apoptosis through increased TNF-α and IL-1ß levels. Exercise partially prevents this phenomenon suggesting that exercise training may provide neuroprotective benefits from cerebral ischemic hyperglycemia.

Capsiate improves glucose metabolism by improving insulin sensitivity better than capsaicin in diabetic rats.

Red peppers and red pepper paste are reported to have anti-obesity, analgesic and anti-inflammatory effects in animals and humans due to the capsaicin in red pepper. We investigated whether consuming capsaicin and capsiate, a nonpungent capsaicin analogue, modifies glucose-stimulated insulin secretion, pancreatic ß-cell survival and insulin sensitivity in 90% pancreatectomized (Px) diabetic rats, a moderate and non-obese type 2 diabetic animal model. Px diabetic rats were divided into 3 treatment groups: 1) capsaicin (Px-CPA), 2) capsiate (Px-CPI) or 3) dextrose (Px-CON) and provided high fat diets (40 energy % fat) containing assigned components (0.025% capsaicin, capsiate, or dextrose) for 8 weeks. Both capsaicin and capsiate reduced body weight gain, visceral fat accumulation, serum leptin levels and improved glucose tolerance without modulating energy intake in diabetic rats. In comparison to the control, both capsaicin and capsiate potentiated first and second and phase insulin secretion during hyperglycemic clamp. Both also increased ß-cell mass by increasing proliferation and decreasing apoptosis of ß-cells by potentiating insulin/IGF-1 signaling. However, only capsiate enhanced hepatic insulin sensitivity during euglycemic hyperinuslinemic clamp. Capsiate reduced hepatic glucose output and increased triglyceride accumulation in the hyperinsulinemic state and capsiate alone significantly increased glycogen storage. This was related to enhanced pAkt→PEPCK and pAMPK signaling. Capsaicin and capsiate reduced triglyceride storage through activating pAMPK. In conclusion, capsaicin and capsiate improve glucose homeostasis but they differently enhance insulin sensitivity in the liver, insulin secretion patterns, and islet morphometry in diabetic rats. Capsiate has better anti-diabetic actions than capsaicin.

Ischemic hippocampal cell death induces glucose dysregulation by attenuating glucose-stimulated insulin secretion which is exacerbated by a high fat diet.

AIMS: Diabetes increases the chances of stroke and the stroke itself is thought to induce hyperglycemia and diabetes. However, this latter contention remains uncorroborated. We investigated whether ischemic hippocampal neuronal cell death induces glucose dysregulation by modulating insulin resistance, glucose-stimulated insulin secretion, and ß-cell mass in Mongolian gerbils fed either a high fat or low fat diet. MAIN METHODS: Gerbils were subjected to either an occlusion of the bilateral common carotid arteries for 8 mins to render them ischemic, or a sham operation. Ischemic gerbils were fed either an 11% fat diet (LFD) or a 40% fat diet (HFD) for 7, 14 or 28 days. KEY FINDINGS: Artery occlusion resulted in a 70% or greater initial reduction in hippocampal CA1 neurons and only HFD decreased the percentage of CA1 neurons as the ischemic periods became longer. Oral glucose tolerance test (OGTT) results revealed that ischemia induced glucose intolerance, and longer ischemic periods and HFD exacerbated this glucose intolerance in ischemic gerbils. Insulin secretion during the OGTT was lower in ischemic gerbils than sham gerbils and the decrease was greatest in the 28 day-HFD among all the groups. Insulin resistance was elevated the most in 28 day-HFD ischemic gerbils. There was a progressive loss of pancreatic ß-cell mass as the post-ischemic time period increased as consequence of HFD; the decrease being caused by increased apoptosis. This increase in apoptosis was partly associated with increased serum levels of IL-1ß, TNF-α and non-esterified fatty acids. SIGNIFICANCE: Hippocampal neuronal cell death deteriorates glucose homeostasis initially through the modulation of insulin secretion and also causes a decrease in ß-cell mass while HFD negatively impacts glucose regulation.

A ketogenic diet impairs energy and glucose homeostasis by the attenuation of hypothalamic leptin signaling and hepatic insulin signaling in a rat model of non-obese type 2 diabetes.

Ketogenic diets (KTD) are reported to have beneficial effects on the regulation of energy and glucose homeostasis, but remain controversial. We investigated the effects of KTD and ketones on insulin resistance and secretion in non-obese type 2 diabetic rats and their mechanism. KTD (82% energy as fat), intraperitoneal injection of ß-hydroxybutyrate (IHB; 150 mg/kg bw/12 h) with a control diet (COD; 20% energy as fat) or saline injection with COD was given to 90% pancreatectomized (Px) diabetic rats for five weeks. KTD increased epididymal fat pads and serum leptin levels without increasing energy intake, but IHB decreased them. KTD, but not IHB, attenuated hypothalamic signal transducer and activator of transcription 3 and 5'-adenosine monophosphate-activated protein kinase (AMPK) phosphorylation in KTD. Serum glucagon levels were markedly higher in the KTD group than in other groups. During an oral glucose tolerance test, serum glucose levels slowly increased until 80 min in the KTD group and then decreased very slowly. Insulin secretion capacity during a hyperglycemic clamp was significantly lower in the IHB group than in other groups. However, a euglycemic hyperinsulinemic clamp revealed that KTD decreased glucose infusion rates and increased hepatic glucose output in hyperinsulinemic states while IHB had opposite effects to KTD. The increased hepatic glucose output in KTD was associated with increased hepatic phosphoenolpyruvate carboxykinase expression through attenuated tyrosine phosphorylation of IRS2 and phosphorylation of Akt(Ser473). Hepatic AMPK(Thr172) phosphorylation was reduced in KTD. In conclusion, KTD impairs energy and glucose homeostasis by exacerbating insulin resistance and attenuating hypothalamic leptin signaling in non-obese type 2 diabetic rats. These changes are not associated with increased serum ketone levels.