Bouts Of Hypoglycemia Research Articles

Idiopathic ketotic hypoglycemia in children: an update.

Idiopathic ketotic hypoglycemia (IKH) is defined as bouts of hypoglycemia with increased blood or urine ketones in certain children after prolonged fasting or during illness. IKH is divided into physiological IKH, which is most frequently observed in normal children with intercurrent acute illness, and pathological IKH, which occurs in children who lack counter-regulatory hormones, have a metabolic disease, or have Silver-Russell syndrome. The typical patient is a young child between the ages of 10 months and 6 years. Episodes nearly always occur in the morning after overnight fasting. Symptoms include those of neuroglycopenia, ketosis, or both. IKH may be diagnosed after ruling out various metabolic and hormonal conditions associated with ketotic hypoglycemia. Sufficient amounts of carbohydrates and protein, avoidance of prolonged fasting, and increased frequency of food ingestion are the main modes of treating IKH. It is crucial to understand the pathogenesis of IKH and to distinguish physiological IKH from pathological IKH. In this mini-review, we present a brief summary of IKH in terms of its definition, types, clinical presentation, diagnosis, and therapeutic approach in children.

Classification and prediction of hypoglycemia in diabetic patients using machine learning techniques

Type 1 diabetics can lower their risk of microvascular and macrovascular problems by carefully regulating their blood glucose levels. The downside is that these measures are incredibly challenging because of the wide diversity across individuals, as well as other factors that affect glycemic management. Keeping glucose levels under control is difficult due to the possibility of severe hypoglycemia in patients receiving intensive insulin therapy. In people with diabetes, hypoglycemia is a common complication, which has a negative impact on overall health and well-being. Improving patient safety by anticipating unfavourable glycemic events has become a practical approach to enhanced patient safety using machine learning decision assistance. This paper suggests the use of three machine learning techniques to solve the problem of diabetic safety: (1) Random Forest for continuous glucose predictions, (2) support vector machines for postprandial period predictions, and (3)artificial neural networks for overnight hypoglycemic predictions. It has the two different categorization and prediction capabilities already established. A major system feature is the overall reduction in bouts of hypoglycemia, which results in an increase in patient safety and provides better confidence in treatment decisions.

Carvedilol Prevents Counterregulatory Failure in Recurrently Hypoglycemic Rats

We showed previously that recurring activation of β2-adrenergic receptors in the ventromedial hypothalamus (VMH) leads to the development of counterregulatory failure, in part by increasing local lactate levels. The current study evaluates whether the non-selective β-blocker, carvedilol, can be used to prevent the development of counterregulatory failure and improve hypoglycemia awareness (HA) in recurrently hypoglycemic (RH) rats. Sprague-Dawley rats (n=6-10 per group) underwent surgery for the implantation of vascular catheters and intracranial guide cannulas that targeted the VMH. These animals then received either 3 bouts of insulin-induced hypoglycemia (RH) over the course of 3 days or they received 3 injections of saline (Controls). A subgroup of RH rats was treated with carvedilol (3mg/kg QID; IP) beginning one day prior to the start of RH and continuing through to the last episode of hypoglycemia. Following the last bout of hypoglycemia, the animals underwent a hypoglycemic clamp with microdialysis to evaluate changes in central lactate and hormone levels. Compared to controls, RH increased VMH lactate by 1.7-fold (P<0.03) and this was associated with an impaired counterregulatory response to hypoglycemia (glucagon and epinephrine responses were reduced by ∼45% and ∼73%, respectively, P<0.04), as expected. Treatment of RH animals with carvedilol restored VMH lactate levels and improved the counterregulatory responses to hypoglycemia. To assess whether carvedilol improved HA, we treated rats that were made “hypoglycemia unaware” with repeated 2-deoxyglucose (2DG; 200mg/kg, SQ) injections with carvedilol and measured food intake in response to insulin-induced hypoglycemia as a surrogate marker for HA. Compared to Controls, 2DG reduced food intake in response to hypoglycemia and treatment with carvedilol increased food intake in 2DG rats (P<0.01). We conclude that carvedilol may be a useful therapeutic strategy to prevent counterregulatory failure and improve HA in RH rats. Disclosure R. Farhat: None. G. Su: None. O. Chan: None.

Glycogen Is the Major Source of Lactate in the Ventromedial Hypothalamus of Recurrently Hypoglycemic Rats

Lactate is an important metabolic substrate for sustaining brain energy demands when glucose supplies are limited. Recurrent hypoglycemia (RH) leads to increased lactate levels in the ventromedial hypothalamus (VMH) which contributes to counterregulatory failure, but the source of this lactate remains unclear. It has been shown that astrocytic glycogen can be broken down into lactate in the brain. Therefore, the present study investigates whether glycogen serves as the major source of lactate in the VMH of RH rats. To address this question, Sprague-Dawley rats were implanted with mini-osmotic pumps and bilateral intracranial guide cannulas that targeted the VMH to deliver either artificial extracellular fluid (aECF) or the glycogen phosphorylase (GP) inhibitor, 1,4-dideoxy-1,4-imino-d-arabinitol (DAB). Subsequently, the rats underwent 3 bouts of hypoglycemia before undergoing a hyperinsulinemic-hypoglycemic clamp on day 4 (n=6/group). A separate group of rats receiving aECF into the VMH were given 3 saline injections as controls before undergoing a hypoglycemic clamp on day 4 (n=6). During the clamps, microdialysis was used to measure VMH lactate levels and VMH glycogen content was determined at the end of the clamp from liquid nitrogen fixed brain samples. VMH lactate levels were elevated in RH rats compared to hypoglycemia-naïve controls (3.6±0.2 vs. 2.3±0.4 mM; P=0.03) and this was associated with impairments in the counterregulatory responses (37% and 45% reduction in glucagon and epinephrine, respectively; P<0.05). Compared to the RH rats, inhibition of GP with DAB prevented the breakdown of VMH glycogen in RH rats (5.3±0.5 vs. 2.4±0.5 μmol/g tissue; P<0.002), prevented the rise in VMH lactate levels (1.5±0.3 vs. 3.6±0.2 mM; P<0.001) and prevented the onset of counterregulatory failure (glucagon and epinephrine responses were similar to controls, P=NS). Our data suggests that astrocytic glycogen likely serves as the primary source of lactate in the VMH of RH rats. Disclosure G. Su: None. O. Chan: None. R. Farhat: None. K. Chapman: None.

Somatostatin Receptor II Antagonism Improves Glucagon Counterregulatory Responses to Recurrent Hypoglycemia in Male Sprague-Dawley Rats

Glucagon (GCN) helps prevent hypoglycemia when blood glucose levels drop; however, recurrent hypoglycemia attenuates GCN counterregulation to subsequent bouts of hypoglycemia. As somatostatin normally inhibits GCN secretion, we tested the hypothesis that a somatostatin receptor type 2 antagonist (SSTR2a), PRL-2903, improves GCN responses attenuated by recurrent hypoglycemia in healthy rats. Healthy male Sprague-Dawley rats (n=22) were made hypoglycemic on three consecutive days (days 1-3, blood glucose 1.7-2.2 mmol/L for ∼2 h) via exogenous insulin administration (10-, 8- and 5- U/kg of Humulin-R on days 1-3, respectively). GCN levels during hypoglycemia on day 3 were significantly lower than on day 1 (117±47 pg/mL vs. 184±77 [mean±SD] pg/mL; P=0.001), highlighting the role of recurrent hypoglycemia in counterregulatory failure. On day 4, rats were treated with either PRL-2903 (10 mg/kg IP; n=13) or vehicle (n=9) 1 h prior to the induction of hypoglycemia with 5 U/kg of R-insulin. GCN levels during hypoglycemia (i.e., glucose ≤3.5 mmol/L) were 2.5-fold higher (109±55 vs. 44±26 pg/mL; P=0.004) compared to vehicle, and time to reach hypoglycemia was 3.2-fold longer (64±45 vs. 20±10 min; P =0.001), with PRL-2903 pre-treatment. Interestingly, C-peptide levels were also lower (P=0.001) with PRL-2903 (0.35±0.22 ng/mL), compared to vehicle (0.63±0.21 ng/mL), inferring a lower insulin secretion during hypoglycemia with PRL-2903 treatment. In conclusion, our data suggests that SSTR2a improves GCN responses following recurrent hypoglycemia, and that this improvement may be associated with a reduction in insulin secretion in healthy rats. Therefore, SSTR2a treatment may be a useful therapeutic approach to improve GCN counterregulatory responses to hypoglycemia. Disclosure M. Riddell: Speaker's Bureau; Self; Medtronic. Consultant; Self; Eli Lilly and Company, JAEB Center For Health Research, Xeris Pharmaceuticals, Inc.. Research Support; Self; Insulet Corporation. Speaker's Bureau; Self; Insulet Corporation. Advisory Panel; Self; Sanofi. Speaker's Bureau; Self; Ascensia Diabetes Care. Stock/Shareholder; Self; Zucara Theraputics. Other Relationship; Self; JDRF. M. Jahangiriesmaili: None. E.R. Mandel: None. C.A. Greenberg: None. A.M. Pasieka: None. T. Teich: None. O. Chan: None. R.T. Liggins: Employee; Self; Zucara Therapeuytics, Inc..

Altered Plasticity of Glycogen Phosphorylase in Forebrain Gliosomes Obtained from Insulinoma Patients.

We investigated a control model of hypoglycemia-exposed brain tissues from a small series of patients with insulinoma, immediately dissect them, and perform a differential cold centrifugation to obtain gliosomes and examine alterations of glycogenolytic mechanisms. The BB as well as MM isoforms of glycogen phosphorylase enzymatic protein expression remained unaltered between insulinoma and control subjects within the gliosomes. However, the glycogen phosphorylase remained in a form that was potentially activated several folds on placing the gliosomes in a glucose-free medium. This was examined by its increased interaction with protein kinase A. Inhibitors of glycogen phosphorylase was used as controls. Furthermore, we demonstrated that glucose-depleted medium enhanced production of both ATP and lactate by the gliosomes. It is possible that a portion of glucose obtained from glycogen breakdown was circuited through glycolytic pathways to generate ATP. It has been reported earlier that ATP within gliosomes plays a major role in glutamate uptake, thus potentially preventing seizure during active bouts of hypoglycemia. Lactate shuttle from astrocytes is a potential mechanism to balance neuronal bioenergetics during events of hypoglycemia. Newer approaches to pharmacologically modulate glycogen phosphorylase may prove to be rational approach for neuroprotective therapy in this common clinical syndrome of hypoglycemia.

Antecedent Hindbrain Glucoprivation Does Not Impair the Counterregulatory Response to Hypoglycemia

Recurrent hypoglycemia impairs hormonal counterregulatory responses (CRRs) to further bouts of hypoglycemia. The hypothalamus and hindbrain are both critical for sensing hypoglycemia and triggering CRRs. Hypothalamic glucose sensing sites are implicated in the pathogenesis of defective CRRs; however, the contribution of hindbrain glucose sensing has not been elucidated. Using a rat model, we compared the effect of antecedent glucoprivation targeting hindbrain or hypothalamic glucose sensing sites with the effect of antecedent recurrent hypoglycemia on CRR to hypoglycemia induced 24 h later. Recurrent hypoglycemia decreased sympathoadrenal (1,470 +/- 325 vs. 3,811 +/- 540 pg/ml in controls [t = 60 min], P = 0.001) and glucagon secretion (222 +/- 43 vs. 494 +/- 56 pg/ml in controls [t = 60]), P = 0.003) in response to hypoglycemia. Antecedent 5-thio-glucose (5TG) injected into the hindbrain did not impair sympathoadrenal (3,806 +/- 344 pg/ml [t = 60]) or glucagon (513 +/- 56 pg/ml [t = 60]) responses to subsequent hypoglycemia. However, antecedent 5TG delivered into the third ventricle was sufficient to blunt CRRs to hypoglycemia. These results show that hindbrain glucose sensing is not involved in the development of defective CRRs. However, neural substrates surrounding the third ventricle are particularly sensitive to glucoprivic stimulation and may contribute importantly to the development of defective CRRs.