scholarly journals Hypothalamic AMP-activated protein kinase activation with AICAR amplifies counterregulatory responses to hypoglycemia in a rodent model of type 1 diabetes

2009 ◽  
Vol 296 (6) ◽  
pp. R1702-R1708 ◽  
Author(s):  
X. Fan ◽  
Y. Ding ◽  
S. Brown ◽  
L. Zhou ◽  
M. Shaw ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Protein Kinase ◽  
Ventromedial Hypothalamus ◽  
Glucose Sensing ◽  
Rodent Model ◽  
Saline Control ◽  
Chronic Hyperglycemia ◽  
Bb Rats ◽  
Amp Activated Protein Kinase

In nondiabetic rodents, AMP-activated protein kinase (AMPK) plays a role in the glucose-sensing mechanism used by the ventromedial hypothalamus (VMH), a key brain region involved in the detection of hypoglycemia. However, AMPK is regulated by both hyper- and hypoglycemia, so whether AMPK plays a similar role in type 1 diabetes (T1DM) is unknown. To address this issue, we used four groups of chronically catheterized male diabetic BB rats, a rodent model of autoimmune T1DM with established insulin—requiring diabetes (40 ± 4 pmol/l basal c-peptide). Two groups were subjected to 3 days of recurrent hypoglycemia (RH), while the other two groups were kept hyperglycemic [chronic hyperglycemia (CH)]. All groups subsequently underwent hyperinsulinemic hypoglycemic clamp studies on day 4 in conjunction with VMH microinjection with either saline (control) or AICAR (5-aminoimidazole-4-carboxamide) to activate AMPK. Compared with controls, local VMH application of AICAR during hypoglycemia amplified both glucagon [means ± SE, area under the curve over time (AUC/ t) 144 ± 43 vs. 50 ± 11 ng·l−1·min−1; P < 0.05] and epinephrine [4.27 ± 0.96 vs. 1.06 ± 0.26 nmol·l−1·min−1; P < 0.05] responses in RH-BB rats, and amplified the glucagon [151 ± 22 vs. 85 ± 22 ng·l−1·min−1; P < 0.05] response in CH-BB rats. We conclude that VMH AMPK also plays a role in glucose-sensing during hypoglycemia in a rodent model of T1DM. Moreover, our data suggest that it may be possible to partially restore the hypoglycemia-specific glucagon secretory defect characteristic of T1DM through manipulation of VMH AMPK.

scholarly journals AMP-activated protein kinase rescues the angiogenic functions of endothelial progenitor cells via manganese superoxide dismutase induction in type 1 diabetes

2011 ◽  
Vol 300 (6) ◽  
pp. E1135-E1145 ◽  
Author(s):  
Xiao-Rong Wang ◽  
Ming-Wei Zhang ◽  
Dan-Dan Chen ◽  
Yun Zhang ◽  
Alex F. Chen
Keyword(s):  
Type 1 Diabetes ◽  
Superoxide Dismutase ◽  
Protein Kinase ◽  
Progenitor Cells ◽  
Manganese Superoxide Dismutase ◽  
Ampk Activation ◽  
Mitochondrial Superoxide ◽  
Manganese Superoxide ◽  
Amp Activated Protein Kinase

Endothelial progenitor cells (EPCs) play an essential role in angiogenesis but are functionally impaired in diabetes. We recently reported that decreased expression of manganese superoxide dismutase (MnSOD) critically contributes to diabetic EPC dysfunction. AMP-activated protein kinase (AMPK) activation has been shown to induce MnSOD and suppress hyperglycemia-induced mitochondrial ROS production in endothelial cells. However, whether AMPK protects EPCs from oxidative stress in diabetes is unknown. We tested the hypothesis that AMPK activation rescues impaired EPC functions through MnSOD induction in type 1 diabetes. Bone marrow-derived EPCs from adult male streptozotocin-induced diabetic mice and normal controls were used. AMPK activity was decreased in diabetic EPCs, indicated by reduced AMPK and acetyl-CoA carboxylase phosphorylation. AMPK activation by treating diabetic EPCs with its selective agonist AICAR rescued their in vitro functions, including Matrigel tube formation, adhesion, and migration. Furthermore, AICAR restored the decreased MnSOD protein and enzymatic activity and suppressed the mitochondrial superoxide level in diabetic EPCs, indicated by MitoSOX flow cytometry. These beneficial effects of AICAR on MnSOD and EPC functions were significantly attenuated by silencing MnSOD or AMPK antagonist compound C pretreatment. Finally, the expression of protein phosphatase 2A, a key enzyme for AMPK dephosphorylation and inactivation, was increased in diabetic EPCs, and its inhibition by siRNA or okadaic acid reversed the deficient AMPK activation and MnSOD level in diabetic EPCs. These findings demonstrate for the first time that AMPK activation rescues impaired EPC functions and suppresses mitochondrial superoxide by inducing MnSOD in type 1 diabetes.

1666-P: Increased Levels of Autophagy in a Rodent Model of Type 1 Diabetes

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 1666-P
Author(s):  
CEREN KARACAY ◽  
PETRA KOTZBECK ◽  
BARBARA PRIETL ◽  
CLEMENS HARER ◽  
THOMAS PIEBER
Keyword(s):  
Type 1 Diabetes ◽  
Rodent Model

scholarly journals A Comparison of Feature Selection and Forecasting Machine Learning Algorithms for Predicting Glycaemia in Type 1 Diabetes Mellitus

2021 ◽  
Vol 11 (4) ◽  
pp. 1742
Author(s):  
Ignacio Rodríguez-Rodríguez ◽  
José-Víctor Rodríguez ◽  
Wai Lok Woo ◽  
Bo Wei ◽  
Domingo-Javier Pardo-Quiles
Keyword(s):  
Diabetes Mellitus ◽  
Machine Learning ◽  
Type 1 Diabetes ◽  
Feature Selection ◽  
Blood Glucose ◽  
Type 1 Diabetes Mellitus ◽  
Support Vector ◽  
Chronic Hyperglycemia ◽  
Predictive Algorithms

Type 1 diabetes mellitus (DM1) is a metabolic disease derived from falls in pancreatic insulin production resulting in chronic hyperglycemia. DM1 subjects usually have to undertake a number of assessments of blood glucose levels every day, employing capillary glucometers for the monitoring of blood glucose dynamics. In recent years, advances in technology have allowed for the creation of revolutionary biosensors and continuous glucose monitoring (CGM) techniques. This has enabled the monitoring of a subject’s blood glucose level in real time. On the other hand, few attempts have been made to apply machine learning techniques to predicting glycaemia levels, but dealing with a database containing such a high level of variables is problematic. In this sense, to the best of the authors’ knowledge, the issues of proper feature selection (FS)—the stage before applying predictive algorithms—have not been subject to in-depth discussion and comparison in past research when it comes to forecasting glycaemia. Therefore, in order to assess how a proper FS stage could improve the accuracy of the glycaemia forecasted, this work has developed six FS techniques alongside four predictive algorithms, applying them to a full dataset of biomedical features related to glycaemia. These were harvested through a wide-ranging passive monitoring process involving 25 patients with DM1 in practical real-life scenarios. From the obtained results, we affirm that Random Forest (RF) as both predictive algorithm and FS strategy offers the best average performance (Root Median Square Error, RMSE = 18.54 mg/dL) throughout the 12 considered predictive horizons (up to 60 min in steps of 5 min), showing Support Vector Machines (SVM) to have the best accuracy as a forecasting algorithm when considering, in turn, the average of the six FS techniques applied (RMSE = 20.58 mg/dL).

scholarly journals Glucose regulates AMP-activated protein kinase activity and gene expression in clonal, hypothalamic neurons expressing proopiomelanocortin: additive effects of leptin or insulin

2007 ◽  
Vol 192 (3) ◽  
pp. 605-614 ◽  
Author(s):  
Fang Cai ◽  
Armen V Gyulkhandanyan ◽  
Michael B Wheeler ◽  
Denise D Belsham
Keyword(s):  
Protein Kinase ◽  
Energy Homeostasis ◽  
Cell Model ◽  
Neuronal Cell ◽  
Cell Types ◽  
Glucose Sensing ◽  
Protein Kinase Activity ◽  
Energy Status ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase

The mammalian hypothalamus comprises an array of phenotypically distinct cell types that interpret peripheral signals of energy status and, in turn, elicits an appropriate response to maintain energy homeostasis. We used a clonal representative hypothalamic cell model expressing proopiomelanocortin (POMC; N-43/5) to study changes in AMP-activated protein kinase (AMPK) activity and glucose responsiveness. We have demonstrated the presence of cellular machinery responsible for glucose sensing in the cell line, including glucokinase, glucose transporters, and appropriate ion channels. ATP-sensitive potassium channels were functional and responded to glucose. The N-43/5 POMC neurons may therefore be an appropriate cell model to study glucose-sensing mechanisms in the hypothalamus. In N-43/5 POMC neurons, increasing glucose concentrations decreased phospho-AMPK activity. As a relevant downstream effect, we found that POMC transcription increased with 2.8 and 16.7 mM glucose. Upon addition of leptin, with either no glucose or with 5 mM glucose, we found that leptin decreased AMPK activity in N-43/5 POMC neurons, but had no significant effect at 25 mM glucose, whereas insulin decreased AMPK activity at only 5 mM glucose. These results demonstrate that individual hypothalamic neuronal cell types, such as the POMC neuron, can have distinct responses to peripheral signals that relay energy status to the brain, and will therefore be activated uniquely to control neuroendocrine function.

scholarly journals Day-to-Day Variations in Fasting Plasma Glucose Do Not Influence Gastric Emptying in Subjects With Type 1 Diabetes

2020 ◽  
Author(s):  
Lea Aigner ◽  
Björn Becker ◽  
Sonja Gerken ◽  
Daniel R. Quast ◽  
Juris J. Meier ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Gastric Emptying ◽  
Plasma Glucose ◽  
Fasting Plasma Glucose ◽  
Healthy Subjects ◽  
Diabetic Patients ◽  
Cross Sectional ◽  
Chronic Hyperglycemia ◽  
Fasting Plasma

<b>Objective:</b> Acute experimental variations in glycemia decelerate (hyperglycemia) or accelerate (hypoglycemia) gastric emptying. Whether spontaneous variations in fasting plasma glucose (FPG) have a similar influence on gastric emptying is yet unclear. <p><b>Research design and methods:</b> Gastric emptying of a mixed meal was prospectively studied three times in 20 patients with type 1 diabetes and 10 healthy subjects with normal glucose tolerance using a <sup>13</sup>C-CO<sub>2</sub> octanoate breath test with Wagner-Nelson analysis. The velocity of gastric emptying was related to fasting plasma glucose (FPG) measured before the test (grouped as low, intermediate, or high). In addition, gastric emptying data from 255 patients with type 1 diabetes studied for clinical indications were compared by tertiles of baseline FPG. </p> <p><b>Results:</b> Despite marked variations in FPG (by 4.8 (3.4; 6.2) mmol/l), gastric emptying did not differ between the three prospective examinations in patients with type 1 diabetes (D T<sub>1/2</sub> between highest and lowest FPG: 1 [95 % CI: -35; 37] min; p = 0.90). The coefficient of variation for T<sub>1/2 </sub>determined three times was 21.0 %. Similar results at much lower variations in FPG were found in healthy subjects. In the cross-sectional analysis, gastric emptying did not differ between the tertiles of FPG (D T<sub>1/2</sub> between highest and lowest FPG: 7 [95 % CI: - 10; 23] min; p = 0.66), when FPG varied by 7.2 (6.7; 7.8) mmol/l. However, higher HbA<sub>1c</sub> was significantly related to slower gastric emptying.</p> <p><b>Conclusions:</b> Day-to-day variations in FPG not induced by therapeutic measures do not influence gastric emptying significantly. These findings are in contrast with those obtained after rapidly clamping plasma glucose in the hyper- or hypoglycemic concentrations range and challenge the clinical importance of short-term glucose fluctuations for gastric emptying in type 1-diabetic patients. Rather, chronic hyperglycemia is associated with slowed gastric emptying.</p>

scholarly journals THE EFFECT OF CHRONIC HYPERGLYCEMIA ON THE STATE OF MUSCULOSKELETAL SYSTEM (LITERATURE REVIEW)

2021 ◽  
Vol 21 (1) ◽  
pp. 184-187
Author(s):  
A.O. Ponyrko
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Bone Tissue ◽  
Musculoskeletal System ◽  
Metabolic Disorder ◽  
Skeletal System ◽  
Complex Disorders ◽  
Chronic Hyperglycemia ◽  
Wide Range

Diabetes mellitus is a metabolic disorder that today has become a threatening problem for human health. Its prevalence has been constantly increasing throughout the world over the past decades. Diabetes mellitus is regarded as an incurable metabolic disorder characterized by hyperglycemia, which is caused by defects in insulin secretion. This disease annually affects almost 3% of the total population of the planet. Chronic hyperglycemia causes dysfunction of various organs of the body, such as the eyes, kidneys, heart, blood vessels, and nerves. The most common complications of diabetes include lesions of the vessels of the eye, kidneys, lower limbs and nervous system. A high level of glucose in the blood causes the development of a wide range of pathological disorders, which affect bones as well. Recent studies have shown that diseases of the skeletal system are often observed in diabetes mellitus. Speaking about the effect of hyperglycemia on bones, the development of osteopenia and osteoporosis should be noted. In this regard, an important area of research is to study changes in the bone tissue in patients with type 1 diabetes mellitus and the mechanisms that lead to disruption of bone structure and metabolism. The article highlights the pathophysiological mechanisms of hyperglycemia action in type 1 diabetes that explains complex disorders of the organs of the musculoskeletal system. The detrimental effect of hyperglycemia results in marked degenerative changes in bone cells. The pathogenic effect of hyperglycemia on bone tissue is manifested in a decrease in bone mineral density that is due to the lack of insulin and, as a consequence, significant metabolic disorders, a decrease in bone mass, inhibition of bone tissue formation, a significant decrease in the trace element composition of bone. The combination of these factors creates the appropriate pathomorphological basis for the development of diabetic osteopathy. The article highlights the mechanism of action of hyperglycemia on skeletal system in order to stimulate to a more detailed investigation of diabetes mellitus in experimental animals.

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