Insulin-Induced Recurrent Hypoglycemia Up-Regulates Glucose Metabolism in the Brain Cortex of Chemically Induced Diabetic Rats

Diabetes is a chronic metabolic disease that seriously compromises human well-being. Various studies highlight the importance of maintaining a sufficient glucose supply to the brain and subsequently safeguarding cerebral glucose metabolism. The goal of the present work is to clarify and disclose the metabolic alterations induced by recurrent hypoglycemia in the context of long-term hyperglycemia to further comprehend the effects beyond brain harm. To this end, chemically induced diabetic rats underwent a protocol of repeatedly insulin-induced hypoglycemic episodes. The activity of key enzymes of glycolysis, the pentose phosphate pathway and the Krebs cycle was measured by spectrophotometry in extracts or isolated mitochondria from brain cortical tissue. Western blot analysis was used to determine the protein content of glucose and monocarboxylate transporters, players in the insulin signaling pathway and mitochondrial biogenesis and dynamics. We observed that recurrent hypoglycemia up-regulates the activity of mitochondrial hexokinase and Krebs cycle enzymes (namely, pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and succinate dehydrogenase) and the protein levels of mitochondrial transcription factor A (TFAM). Both insults increased the nuclear factor erythroid 2–related factor 2 (NRF2) protein content and induced divergent effects in mitochondrial dynamics. Insulin-signaling downstream pathways were found to be down-regulated, and glycogen synthase kinase 3 beta (GSK3β) was found to be activated through both decreased phosphorylation at Ser9 and increased phosphorylation at Y216. Interestingly, no changes in the levels of cAMP response element-binding protein (CREB), which plays a key role in neuronal plasticity and memory, were caused by hypoglycemia and/or hyperglycemia. These findings provide experimental evidence that recurrent hypoglycemia, in the context of chronic hyperglycemia, has the capacity to evoke coordinated adaptive responses in the brain cortex that will ultimately contribute to sustaining brain cell health.

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Gosha-jinki-gan (a Herbal Complex) Corrects Abnormal Insulin Signaling

Evidence-based Complementary and Alternative Medicine ◽

10.1093/ecam/neh028 ◽

2004 ◽

Vol 1 (3) ◽

pp. 269-276 ◽

Cited By ~ 16

Author(s):

Bolin Qin ◽

Masaru Nagasaki ◽

Ming Ren ◽

Gustavo Bajotto ◽

Yoshiharu Oshida ◽

...

Keyword(s):

Skeletal Muscle ◽

Insulin Receptor ◽

Protein Content ◽

Insulin Signaling ◽

Molecular Mechanisms ◽

Diabetic Rats ◽

Metabolic Clearance ◽

Long Term Effects ◽

Β Protein

Previous studies have shown that the traditional herbal complex Gosha-jinki-gan (GJG) improves diabetic neuropathy and insulin resistance. The present study was undertaken to elucidate the molecular mechanisms related with the long-term effects of GJG administration on insulin actionin vivoand the early steps of insulin signaling in skeletal muscle in streptozotocin (STZ) diabetes. Rats were randomized into five subgroups: (1) saline treated control, (2) GJG treated control, (3) 2-unit insulin + saline treated diabetic, (4) saline + GJG treated diabetic and (5) 2-unit insulin + GJG treated diabetic groups. After seven days of treatment, euglycemic clamp experiment at an insulin infusion rate of 6 mU/kg/min was performed in overnight fasted rats. Despite the 2-unit insulin treatment, the metabolic clearance rates of glucose (MCR, ml/kg/min) in diabetic rats were significantly lower compared with the controls (11.4 ± 1.0 vs 44.1 ± 1.5;P< 0.001), and were significantly improved by insulin combined with GJG or GJG alone (26 ± 3.2 and 24.6 ± 2.2,P< 0.01, respectively). The increased insulin receptor (IR)-β protein content in skeletal muscle of diabetic rats was not affected by insulin combined with GJG administration. However, the decreased insulin receptor substrate-1 (IRS-1) protein content was significantly improved by treatment with GJG. Additionally, the increased tyrosine phosphorylation levels of IR-β and IRS-1 were significantly inhibited in insulin combined with GJG treated diabetes. The present results suggest that the improvement of the impaired insulin sensitivity in STZ-diabetic rats by administration of GJG may be due, at least in part, to correction in the abnormal early steps of insulin signaling in skeletal muscle.

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Comparison of the Neuroprotective Effects of Aspirin, Atorvastatin, Captopril and Metformin in Diabetes Mellitus

Biomolecules ◽

10.3390/biom9040118 ◽

2019 ◽

Vol 9 (4) ◽

pp. 118 ◽

Cited By ~ 6

Author(s):

Maryam Paseban ◽

Reza Mohebbati ◽

Saeed Niazmand ◽

Thozhukat Sathyapalan ◽

Amirhossein Sahebkar

Keyword(s):

Brain Cortex ◽

Diabetic Rats ◽

High Dose ◽

Neuroprotective Effects ◽

Treatment Groups ◽

Oxidative Markers ◽

Combined Use ◽

C 50 ◽

The Brain ◽

High Dose Aspirin

Objective: The aim of this study was to investigate the effect of combined intake of a high dose of aspirin, atorvastatin, captopril and metformin on oxidative stress in the brain cortex and hippocampus of streptozotocin (STZ)-induced diabetic rats. Material and methods: Rats were randomly divided into the following 11 groups: control and diabetic (D), as well as 9 groups that were treated with metformin (M, 300 mg/kg) or aspirin (ASA, 120 mg/kg) alone or in different combinations with captopril (C, 50 mg/kg) and/or atorvastatin (AT, 40 mg/kg) as follows: (D + M), (D + ASA), (D + M + ASA), (D + M + C), (D + M + AT), (D + M + C + ASA), (D + M + C + AT), (D + M + AT + ASA) and (D + M + C + AT + ASA). The rats in treatment groups received drugs by gavage daily for six weeks. Serum lipid profile and levels of oxidative markers in the brain cortex and hippocampus tissues were evaluated. Results: The levels of malondialdehyde in the brain cortex and hippocampus in all the treated groups decreased significantly (p < 0.05). There was a significant increase in the total thiol concentration as well as catalase activity in treated rats in (M + AT), (M + C + ASA), (M + C + AT), (M + AT + ASA) and (M + C + AT + ASA) groups in cortex and hippocampus in comparison with the diabetic rats (p < 0.05). Also, the superoxide dismutase activity in all treated rats with medications was significantly increased compared to the diabetic rats (p < 0.05–0.01). Conclusion: Our findings showed that the combined use of high-dose aspirin, metformin, captopril and atorvastatin potentiated their antioxidant effects on the brain, and hence could potentially improve cognitive function with their neuroprotective effects on hippocampus.

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P3-027: A Molecular Study on the Neuroprotective Effect of Nigella Sativa Oil on Insulin Signaling Pathways in the Brain of Type 2 Diabetic Rats

Alzheimer s & Dementia ◽

10.1016/j.jalz.2016.06.1684 ◽

2016 ◽

Vol 12 ◽

pp. P827-P827

Author(s):

Shaymaa Abdulmalek ◽

Sofia Risk ◽

Mahmoud Balbaa

Keyword(s):

Signaling Pathways ◽

Insulin Signaling ◽

Nigella Sativa ◽

Neuroprotective Effect ◽

Molecular Study ◽

Diabetic Rats ◽

Nigella Sativa Oil ◽

The Brain ◽

Type 2 Diabetic

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A 70% Ethanol Extract of Mistletoe Rich in Betulin, Betulinic Acid, and Oleanolic Acid Potentiatedβ-Cell Function and Mass and Enhanced Hepatic Insulin Sensitivity

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2016/7836823 ◽

2016 ◽

Vol 2016 ◽

pp. 1-13 ◽

Cited By ~ 7

Author(s):

Byoung-Seob Ko ◽

Suna Kang ◽

Bo Reum Moon ◽

Jin Ah Ryuk ◽

Sunmin Park

Keyword(s):

Cell Proliferation ◽

Insulin Secretion ◽

Glucose Metabolism ◽

Oleanolic Acid ◽

Normal Control ◽

Insulin Signaling ◽

Betulinic Acid ◽

Diabetic Rats ◽

Glucose Output ◽

Insulinoma Cells

We investigated that the long-term consumption of the water (KME-W) and 70% ethanol (KME-E) mistletoe extracts had antidiabetic activities in partial pancreatectomized (Px) rats. Px rats were provided with a high-fat diet containing 0.6% KME-E, 0.6% KME-W, and 0.6% dextrin (control) for 8 weeks. As normal-control, Sham-operated rats were provided with 0.6% dextrin. In cell-based studies, the effects of its main terpenoids (betulin, betulinic acid, and oleanolic acid) on glucose metabolism were measured. Both KME-W and KME-E decreased epididymal fat mass by increasing fat oxidation in diabetic rats. KME-E but not KME-W exhibited greater potentiation of first-phase insulin secretion than the Px-control in a hyperglycemic clamp. KME-E also madeβ-cell mass greater than the control by increasingβ-cell proliferation and decreasing its apoptosis. In a euglycemic-hyperinsulinemic clamp, whole-body glucose infusion rate and hepatic glucose output increased with potentiating hepatic insulin signaling in the following order: Px-control, KME-W, KME-E, and normal-control. Betulin potentiated insulin-stimulated glucose uptake via increased PPAR-γactivity and insulin signaling in 3T3-L1 adipocytes, whereas oleanolic acid enhanced glucose-stimulated insulin secretion and cell proliferation in insulinoma cells. In conclusion, KME-E prevented the deterioration of glucose metabolism in diabetic rats more effectively than KME-W and KME-E can be a better therapeutic agent for type 2 diabetes than KME-W.

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Neuronal LRP1 Regulates Glucose Metabolism and Insulin Signaling in the Brain

Journal of Neuroscience ◽

10.1523/jneurosci.5180-14.2015 ◽

2015 ◽

Vol 35 (14) ◽

pp. 5851-5859 ◽

Cited By ~ 65

Author(s):

C.-C. Liu ◽

J. Hu ◽

C.-W. Tsai ◽

M. Yue ◽

H. L. Melrose ◽

...

Keyword(s):

Glucose Metabolism ◽

Insulin Signaling ◽

The Brain

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Glycolysis-Induced Discordance between Glucose Metabolic Rates Measured with Radiolabeled Fluorodeoxyglucose and Glucose

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1989.111 ◽

1989 ◽

Vol 9 (6) ◽

pp. 774-785 ◽

Cited By ~ 101

Author(s):

Robert F. Ackermann ◽

James L. Lear

Keyword(s):

Glucose Metabolism ◽

Optic Tectum ◽

Krebs Cycle ◽

Lactate Production ◽

Metabolic Rates ◽

Glycolytic Metabolism ◽

Limbic Structures ◽

Glucose Phosphorylation ◽

The Difference ◽

The Brain

We have developed an autoradiographic method for estimating the oxidative and glycolytic components of local CMRglc (LCMRglc), using sequentially administered [18F]fIuorodeoxyglucose (FDG) and [14C]-6-glucose (GLC). FDG-6-phosphate accumulation is proportional to the rate of glucose phosphorylation, which occurs before the divergence of glycolytic ( GMg) and oxidative ( GMo) glucose metabolism and is therefore related to total cerebral glucose metabolism GMt: GMg + GMo = GMt. With oxidative metabolism, the 14C label of GLC is temporarily retained in Krebs cycle-related substrate pools. We hypothesize that with glycolytic metabolism, however, a significant fraction of the 14C label is lost from the brain via lactate production and efflux from the brain. Thus, cerebral GLC metabolite concentration may be more closely related to GMo than to GMt If true, the glycolytic metabolic rate will be related to the difference between FDG- and GLC-derived LCMRglc. Thus far, we have studied normal awake rats, rats with limbic activation induced by kainic acid (KA), and rats visually stimulated with 16-Hz flashes. In KA-treated rats, significant discordance between FDG and GLC accumulation, which we attribute to glycolysis, occurred only in activated limbic structures. In visually stimulated rats, significant discordance occurred only in the optic tectum.

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