Unchanged hypothalamic neuropeptide Y concentrations in hyperphagic, hypoglycemic rats: evidence for specific metabolic regulation of hypothalamic NPY

Hypothalamic concentrations of neuropeptide Y (NPY), a potent central appetite stimulant, increase dramatically in food-restricted and insulin-deficient diabetic rats. This suggest that NPY may drive hyperphagia in these conditions, which are characterized by weight loss and insulin deficiency. To test the hypothesis that insulin deficiency and weight loss are specific stimuli to hypothalamic NPY, we measured NPY concentrations in individual hypothalamic regions in rats with hyperphagia caused by insulin-induced hypoglycemia. Groups of 8 male Wistar rats were injected with ultralente insulin (20-60 U/kg) to induce either acute hypoglycemia (7 h after a single injection) or chronic hypoglycemia (8 days with daily injections). In hypoglycemic rats, plasma insulin concentrations were increased 6- to 7-fold compared with saline-injected controls; food intake was significantly increased with acute and chronic hypoglycemia and weight gain was significantly increased in the chronically hypoglycemic group. NPY concentrations were measured by radioimmunoassay in 8 hypothalamic regions microdissected from fresh brain slices. NPY concentrations were not increased in any region in either acute or chronic hypoglycemia. NPY therefore seems unlikely to mediate hyperphagia in hyperinsulinemia-induced hypoglycemia, supporting the hypothesis that weight loss is a specific stimulus to hypothalamic NPY and that insulin deficiency may be the metabolic signal responsible.     

Decreased nutrient-stimulated insulin secretion in chronically hypoglycemic late-gestation fetal sheep is due to an intrinsic islet defect

We measured in vivo and in vitro nutrient-stimulated insulin secretion in late gestation fetal sheep to determine whether an intrinsic islet defect is responsible for decreased glucose-stimulated insulin secretion (GSIS) in response to chronic hypoglycemia. Control fetuses responded to both leucine and lysine infusions with increased arterial plasma insulin concentrations (average increase: 0.13 +/- 0.05 ng/ml leucine; 0.99 +/- 0.26 ng/ml lysine). In vivo lysine-stimulated insulin secretion was decreased by chronic (0.37 +/- 0.18 ng/ml) and acute (0.27 +/- 0.19 ng/ml) hypoglycemia. Leucine did not stimulate insulin secretion following acute hypoglycemia but was preserved with chronic hypoglycemia (0.12 +/- 0.09 ng/ml). Isolated pancreatic islets from chronically hypoglycemic fetuses had normal insulin and DNA content but decreased fractional insulin release when stimulated with glucose, leucine, arginine, or lysine. Isolated islets from control fetuses responded to all nutrients. Therefore, chronic late gestation hypoglycemia causes defective in vitro nutrient-regulated insulin secretion that is at least partly responsible for diminished in vivo GSIS. Chronic hypoglycemia is a feature of human intrauterine growth restriction (IUGR) and might lead to an islet defect that is responsible for the decreased insulin secretion patterns seen in human IUGR fetuses and low-birth-weight human infants.     

Lack of effects of an acute hepatic vagotomy on insulin and catecholamine responses in rats following exercise

The purpose of the present investigation was to evaluate the effects of an acute hepatic vagotomy on hormonal responses to hyperglycemic and hypoglycemic challenges in rats previously submitted to an exercise protocol. Two experiments were conducted. In a first experiment, 8-week trained (TR) and untrained (UNTR) rats, subdivided into acutely hepatic vagotomized (HV) and sham-operated (SHM) groups, were submitted to an intraperitoneal glucose tolerance test (0.5 g/kg) under anesthesia. Training was associated with a tendency (P = 0.07) for blood glucose levels to be less elevated (at time point 10 min), and with a significant (P < 0.01) lower glucose/insulin ratio following the glucose injection. The HV did not have any effects on these responses. In a second experiment, non-exercised rats and a group of rats submitted to an acute bout of exercise (treadmill, 60 min, 26 m/min, 5% slope) 24 h before the experiment, each one of these two groups being subdivided into acutely HV and SHM groups, were submitted to an insulin-induced hypoglycemia protocol, under anesthesia. Blood glucose concentrations were decreased significantly (P < 0.01) to approximately 40 mg/dl in all groups 60 and 80 min after the insulin injection. Plasma adrenaline and noradrenaline levels were increased significantly (P < 0.01) in all groups. The catecholamine increase was not influenced by the HV or the acute exercise bout. The present results do not indicate an implication of the hepatic vagus nerve on hormonal responses to hyper and hypoglycemia following exercise.     

A case of autoimmune insulin antibody syndrome associated with polymyositis, empty sella and apparent high urinary output of immunoreactive insulin.

Patients with autoimmune insulin antibody are characterized by hypoglycemic attacks and antibodies to insulin in serum without prior insulin administration. In the present report, a patient with hypoglycemia due to autoimmune insulin antibody associated with primary empty sella syndrome and polymyositis appeared to have high urinary immunoreactive insulin (IRI) in the face of normal urinary C peptide. Consequently, the urinary IRI/C peptide ratio was apparently high. The amelioration of hypoglycemic attacks and polymyositis by prednisolone treatment was accompanied by the disappearance of the antibodies and complete normalization of the urinary IRI and IRI/C peptide ratio. No comparable rise in the urinary IRI and IRI/C peptide ratio was observed in the patients with other disorders studied. Glucose clamp and glucose tolerance study showed decreased sensitivity to exogenous or newly secreted insulin, prolonged half disappearance time of serum insulin, and normal disappearance of blood glucose. These results were consistent with the idea that autoantibodies buffered the effect of exogenous or newly secreted insulin and maintained a relatively constant level of serum free insulin which was not high enough when a large amount of glucose was loaded, but was too high after prolonged fasting, which eventually caused hypoglycemic attacks.     

Susceptibility of the developing brain to acute hypoglycemia involving A1 adenosine receptor activation

It has been suggested that the developing brain is less vulnerable to the adverse effects of hypoglycemia than the mature brain; however, this issue remains controversial. We also do not know the magnitude or duration of hypoglycemia needed to trigger hypoglycemic brain injury during development. To address this issue a series of in vivo and in vitro studies were performed. First, we established an acute model of insulin-induced hypoglycemia in mice by administering 3 U/kg of neutral-protamine Hagadorn insulin subcutaneously. When we examined degenerating neurons in hippocampus and striatum by TUNEL labeling, injury was observed after 4 h of hypoglycemia in postnatal day (P)7 mice, and we observed more cell injury in animals rendered hypoglycemic at P7 than at P21. Studies of hippocampal slice cultures revealed that reduction in glucose concentration induced more neuronal injury in slices prepared from P3 and P7 than from P14 and P21 mice. Treatment of slices with an adenosine A(1) receptor (A(1)AR) antagonist reduced the hypoglycemic damage, whereas agonists increased damage, particularly in slices prepared from very young pups. This suggests a critically important role for A(1)ARs, which was further demonstrated by the reduction of hypoglycemic damage in hippocampal slices prepared from A(1)AR(-/-) mice. Furthermore, insulin-induced hypoglycemia in P7 A(1)AR(-/-) mice did not increase TUNEL-positive cells, but a major increase was seen in A(1)AR(+/-) mice. These observations show that the developing nervous system is indeed sensitive to acute hypoglycemic injury and that A(1)AR activation contributes to damage induced by hypoglycemia, particularly in immature mouse brain.     

Isolated corticotrophin-deficiency found through alcohol-induced hypoglycemic coma.

A case of hypoglycemic coma after alcohol ingestion was observed in a chronic alcoholic. Upon close examination isolated corticotrophin-deficiency was found. It is suggested that ethanol-induced hypoglycemia may be consistent with dysfunction of mitochondria in hepatic cells and that there may be disorder of the hypothalamus in the chronic drinker.     

Prevention and Management of Insulin-Associated Hypoglycemia in Hospitalized Patients

Objective: To determine whether appropriate therapeutic changes in insulin doses are made to prevent and manage insulin-associated hypoglycemic events in non–critically ill hospitalized patients.Methods: This retrospective study was conducted in hospitalized adults on medical or surgical floors with insulin-associated hypoglycemia, excluding treatment with insulin infusions, insulin pumps, and parenteral nutrition. The first hypoglycemic event after 48 hours of admission was the index event. Over the 1-year study period, a total of 457 insulin-associated hypoglycemic events were included as index events.Results: An indication for an insulin dose adjustment was identified in 32 and 42% of patients on day -2 and day -1, respectively, before the index hypoglycemic event, of which 35 and 55%, respectively, had an insulin dose reduction ≥10%. Following the hypoglycemic event, 44% of patients had an insulin dose reduction of ≥20%. Therapeutic reduction of the total daily insulin dose by ≥20% was associated with increased odds of normoglycemia and lower odds of hyperglycemia but was not associated with lower odds of recurrent hypoglycemia on the day following the index hypoglycemic event. There was a high prevalence of hypoglycemic risk factors in this population, with kidney disease and nil per os status being the most prevalent contributing factors.Conclusion: Adherence to the current practice recommendation to reduce insulin doses in patients with borderline hypoglycemia and following overt hypoglycemia was modest. Further studies are needed to understand the associated risks and to define appropriate therapeutic changes for insulin treated patients with borderline and overt hypoglycemia.Abbreviations:AKI = acute kidney injuryBG = blood glucoseCKD = chronic kidney diseaseESRD = end-stage renal diseaseICU = intensive care unitNPH = Neutral Protamine HagedornNPO = nil per osOR = odds ratioTDD = total daily dose     

Acute, same-day effects of antecedent exercise on counterregulatory responses to subsequent hypoglycemia in type 1 diabetes mellitus

Exercise-induced hypoglycemia can occur within hours after exercise in type 1 diabetes mellitus (T1DM) patients. This study tested the hypothesis that an acute exercise bout causes (within hours) blunted autonomic and metabolic responses to subsequent hypoglycemia in patients with T1DM. Twelve T1DM patients (3 W/9 M) were studied during a single-step, 2-h hyperinsulinemic (572 +/- 4 pmol/l) hypoglycemic (2.8 +/- 0.1 mmol/l) clamp 2 h after either a hyperinsulinemic euglycemic (AM EUG) or hypoglycemic clamp (AM HYPO) or after sitting in a chair with basal insulin infusion (AM CON) or 90 min of moderate-intensity exercise (50% Vo(2 max), AM EX). Both AM HYPO and AM EX significantly blunted epinephrine responses and muscle sympathetic nerve activity responses to subsequent hypoglycemia compared with both control groups. Endogenous glucose production was significantly lower and the exogenous glucose infusion rate needed to maintain the hypoglycemic level was significantly greater during subsequent hypoglycemia in AM EX vs. CON. Rate of glucose disposal (Rd) was significantly reduced following AM HYPO. In summary, within 2.5 h, both moderate-intensity AM EX and AM HYPO blunted key autonomic counterregulatory responses. Despite this, glucose Rd was reduced during afternoon hypoglycemia following morning hypoglycemia, indicating posthypoglycemic insulin resistance. After morning exercise, endogenous glucose production was blunted, but glucose Rd was maintained during afternoon hypoglycemia, thereby indicating reduced metabolic defenses against hypoglycemia. These data suggest that exercise-induced counterregulatory failure can occur very rapidly, increasing the risk for hypoglycemia in T1DM within hours.     

Effects of intracerebroventricular administration of the NPY-Y1 receptor antagonist, 1229U91, on hyperphagic and glycemic responses to acute and chronic intermediate insulin-induced hypoglycemia in female rats

Neuropeptide Y (NPY) Y1 receptors are implicated in CNS regulation of food intake, but their role in hypoglycemic hyperphagia remains unclear. The present studies utilized a pharmacological approach to investigate the hypothesis that NPY acts via Y1 receptor-dependent mechanisms to regulate feeding and blood glucose profiles during intermediate insulin-induced hypoglycemia. Groups of ovariectomized, estradiol benzoate-treated female rats were injected subcutaneously with one or four doses of neutral protamine Hagedorn insulin (NPH), on as many days, or with diluent alone. Before final treatments on day four, the animals were pretreated by intracerebroventricular (icv) delivery of the NPY Y1 receptor antagonist, 1229U91, or the vehicle, artificial cerebrospinal fluid (acsf). Food intake during acute hypoglycemia was significantly diminished between t_o and + 2 h in animals pretreated with the Y1 receptor antagonist versus vehicle. Administration of 1229U91 prior to the fourth of four NPH doses suppressed hypoglycemic hyperphagia over a relatively longer interval, e.g. 4 h, after t_o relative to the acute insulin group. Blood glucose levels after a single NPH injection were similar in acsf- and antagonist-pretreated rats at + 2, + 4, and + 6 h, but were lower at + 9 h in the latter group. Pretreatment with 1229U91 did not modify glucose profiles between + 2 and + 9 h after multiple dosing with NPH, but prevented recovery from hypoglycemia at + 12 h. The present results show that central NPY Y1 receptor antagonism inhibits hypoglycemic hyperphagia, and that this suppressive effect on feeding was of greater duration during recurring hypoglycemia. The data also show that Y1 receptor blockade decreases glycemic responses to both single and serial NPH dosing, albeit at different post-injection time points. The current studies support the view that NPY Y1 receptors function within central neural pathways that govern feeding and glycemic responses to intermediate-acting insulin, and that Y1 receptor-mediated stimulation of food intake may habituate in a positive manner to repetitive insulin-induced hypoglycemia. Further research is needed to evaluate the impact of chronic insulin-induced hypoglycemia on neuropeptide Y neurotransmission and Y1 receptor expression within regulatory circuitries that control food intake and glucostasis.     

Effects of Milnacipran in Animal Models of Anxiety and Memory

Serotonin (5-HT) and noradrenaline (NA) are involved in both pathogenesis and recovery from depression and anxiety. We examined the effects of acute and chronic treatment with milnacipran, a serotonin/noradrenaline reuptake inhibitors (SNRIs) antidepressant, on anxiety and memory retention in rats. Male Wistar rats received acute or chronic administration of milnacipran (12.5, 25 or 50 mg/kg) or saline (control group). The animals were separately submitted to elevated plus-maze, inhibitory avoidance and open-field tasks 1 h after injection, in the acute group, or 23 h after last injection, in the chronic group. Our results showed an anxiolytic-like effect after chronic administration of milnacipran at doses of 25 and 50 mg/kg. The treatment does not interfere in memory retention and habituation to a novel environment at any doses studied. These findings support that milnacipran, an established SNRIs antidepressant, can also be useful in the treatment of anxiety disorders.     

Is inflammaging an auto[innate]immunity subclinical syndrome?

The low-grade, chronic, systemic inflammatory state that characterizes the aging process (inflammaging) results from late evolutive-based expression of the innate immune system. Inflammaging is characterized by the complex set of five conditions which can be described as 1. low-grade, 2. controlled, 3. asymptomatic, 4. chronic, 5. systemic, inflammatory state, and fits with the antagonistic pleiotropy theory on the evolution of aging postulating that senescence is the late deleterious effect of genes (pro-inflammatory versus anti-inflammatory)that are beneficial in early life. Evolutionary programming of the innate immune system may act via selection on these genetic traits. Here I propose that the already acquired knowledge in this field may pave the way to a new chapter in the pathophysiology of autoimmunity: the auto-innate-immunity syndromes. Indeed, differently from the well known chapter of conventional autoimmune diseases and syndromes where the main actor is the adaptive immunity, inflammaging may constitute the subclinical paradigm of a new chapter of autoimmunity, namely that arising from an autoimmune inflammatory response of the innate-immune-system, an old actor of immunity and yet a new actor of autoimmunity, also acting as a major determinant of elderly frailty and age-associated diseases.     

Is inflammaging an auto[innate]immunity subclinical syndrome?

The low-grade, chronic, systemic inflammatory state that characterizes the aging process (inflammaging) results from late evolutive-based expression of the innate immune system. Inflammaging is characterized by the complex set of five conditions which can be described as 1. low-grade, 2. controlled, 3. asymptomatic, 4. chronic, 5. systemic, inflammatory state, and fits with the antagonistic pleiotropy theory on the evolution of aging postulating that senescence is the late deleterious effect of genes (pro-inflammatory versus anti-inflammatory)that are beneficial in early life. Evolutionary programming of the innate immune system may act via selection on these genetic traits. Here I propose that the already acquired knowledge in this field may pave the way to a new chapter in the pathophysiology of autoimmunity: the auto-innate-immunity syndromes. Indeed, differently from the well known chapter of conventional autoimmune diseases and syndromes where the main actor is the adaptive immunity, inflammaging may constitute the subclinical paradigm of a new chapter of autoimmunity, namely that arising from an autoimmune inflammatory response of the innate-immune-system, an old actor of immunity and yet a new actor of autoimmunity, also acting as a major determinant of elderly frailty and age-associated diseases.     

Omitting Late-Night Eating May Cause Hypoglycemia in “Well Controlled” Basal Insulin-Treated Type 2 Diabetes

ObjectiveTo assess hypoglycemia caused by eating the last meal of the day earlier or its omission in “well controlled” type 2 diabetes mellitus patients treated with once-nightly basal insulin.MethodsPreviously basal insulin-titrated subjects (n = 20) (fasting plasma glucose, FPG, < 110 mg/dL and no self-reported hypoglycemia) underwent continuous glucose monitoring (CGM) during 3 consecutive eating conditions of 3 days each; (1) usual eating, (2) the last meal restricted to 18:00, and (3) 1 sequential meal omitted/day thereby creating a fasting day after transposing the 4-hour period after a meal with that when the meal was omitted. One 24-hour (00:00 to 00:00) period within each eating condition was selected for comparison.ResultsThe mean duration in all hypoglycemic ranges doubled (P = .0584 or greater) when the last meal was omitted or eaten at 18:09 ± 0:39 instead of 19:43 ± 1:01, the usual time for the subjects’ undisturbed eating. The mean duration of hypoglycemia was greatest between 00:00 to 06:00 compared to the 3 other 6-hour periods of the day.ConclusionsIncreased hypoglycemia occurs when the subject’s last meal is eaten earlier or omitted and may not be recognized because it occurs predominately during sleep. When titrating basal insulin from the morning FPG, considerations should be given to the effect of the last meal of the day and possible hypoglycemia between 00:00 and 06:00 to avoid excessive basal insulin treatment. (Endocr Pract. 2015;21:280-285)     

Impact of hypoglycemia and diabetes on CNS: correlation of mitochondrial oxidative stress with DNA damage

Oxidative stress plays an important role in tissue damage caused by hypoglycemia and diabetes, which may be the result of deterioration in glucose homeostasis caused by these metabolic disorders. The present study examined the effects of insulin-induced hypoglycemia and streptozotocin induced diabetes on mitochondrial lipid peroxidation and antioxidant enzymes from different brain regions, namely, cerebral hemispheres, cerebellum, brain stem and diencephalon. In situ localization of DNA single strand breaks (SSBs) were also studied by DNA polymerase-I mediated biotin dATP labeled nick translation method after inducing hypoglycemia and diabetes. Significant decrease in mitochondrial catalase, manganese superoxide-dismutase (Mn-SOD) and reduced glutathione (GSH) content and increase in the lipid peroxidation (LPx) and glutathione peroxidase (GPx) activity was observed under these metabolic stress conditions with more pronounced effects in hypoglycemic group. We conclude that during severe energy deprivation following hypoglycemia and diabetes, mitochondrial free radicals scavenger system is down regulated, which leads to reactive oxygen species (ROS) generation. High levels of ROS in turn activate the processes leading to DNA damage. DNA SSBs, which indicates nuclear disintegration is an important feature of neuronal cell death.     

NGF and bFGF protect rat hippocampal and human cortical neurons against hypoglycemic damage by stabilizing calcium homeostasis.

NGF and bFGF have recently been shown to have biological activity in central neurons, but their normal functions and mechanisms of action are unknown. Since central neurons are particularly vulnerable to hypoglycemia that occurs with ischemia or insulin overdose, we tested the hypothesis that growth factors can protect neurons against hypoglycemic damage. NGF and bFGF each prevented glucose deprivation-induced neuronal damage in human cerebral cortical and rat hippocampal cell cultures (EGF was ineffective). Protection was afforded when the growth factors were administered before (NGF and bFGF) or up to 12 hr following (NGF) the onset of hypoglycemia. Direct measurements of intracellular calcium levels and manipulations of calcium influx demonstrated that sustained elevations in intracellular calcium levels mediated the hypoglycemic damage. NGF and bFGF each prevented the hypoglycemia-induced elevations of intracellular calcium. These findings indicate that growth factors can stabilize neuronal calcium homeostasis in central neurons and thereby protect them against environmental insults.     

Decreased vascular endothelial growth factor response to acute hypoglycemia in type 2 diabetic patients with hypoglycemic coma

IntroductionPlasma vascular endothelial growth factor (VEGF) was shown to increase during acute hypoglycemia and could mediate rapid adaptation of the brain. In this study we examined the neuroendocrine response in patients with type 2 diabetes mellitus (T2DM) in hypoglycemic coma or with acute neuroglycopenic symptoms.MethodsWe prospectively studied 135 consecutive T2DM patients admitted for severe hypoglycemia during a 2-year period. We collected clinical variables and measured plasma concentrations of VEGF, epinephrine, norepinephrine, cortisol and growth hormone at admission and 30 min afterwards.ResultsThirty two patients developed hypoglycemic coma and 103 did not lose consciousness. Median plasma VEGF level of coma patients was 3.1-fold lower at baseline than that of non-coma patients, and even 5.3-fold lower 30 min afterwards. Plasma epinephrine concentration was significantly lower just at baseline in coma patients. On the contrary, there were no differences in concentrations of the other hormones. Multivariate logistic regression analysis showed that VEGF concentration (OR 0.68; CI 0.51–0.95) was a protective factor against the development of coma.ConclusionsVEGF and epinephrine responses to acute hypoglycemia are reduced in T2DM patients who develop hypoglycemic coma. An increased plasma VEGF concentration appeared to be a protective factor against the development of hypoglycemic coma.     

Cerebral Oxidative Metabolism and Blood Flow During Acute Hypoglycemia and Recovery in Unanesthetized Rats

Abstract: Progressive neurological depression leading to coma was produced in unanesthetized rats at a constant level of hypoglycemia induced by insulin. High-energy phosphate concentrations in brain remained normal during hypoglycemic lethargy, but ATP declined by 6% during stupor and by 40% during coma that was characterized by an isoelectric EEG. Cerebral blood flow (CBF) remained normal during hypoglycemia whereas the cerebral metabolic rates for oxygen (CMRo₂) and glucose (CMR_glucose) decreased by 45 and 73%, respectively, indicating oxidation of nonglucose fuels. A plot of CMRo₂ and CMR_glucose versus plasma glucose indicated increasing oxidation of alternate substrates (elevated CMRo²/CMR_glucose) at plasma glucose concentrations below 2.5 mm . The cerebral uptake of β-hydroxybutyrate increased during hypoglycemic stupor and its complete oxidation could account for the CMRo₂ in excess of glucose utilization. Brain ammonia, a byproduct of amino acid metabolism, reached a level during hypoglycemic coma sufficient to produce coma in normoglycemic animals. The rate and degree of recovery after glucose administration depended on the duration of hypoglycemia and the pretreatment neurological state of the animal. Following 10 min of glucose infusion, ATP levels that were modestly depressed in stuporous rats recovered fully, paralleling the animals' apparently full neurological recovery. Rats that had been in hypoglycemic coma for 1 min or less fully recovered high-energy phosphate concentrations in brain. However, when normalization of plasma glucose was delayed for more than 1 min of coma, the CMRo₂ remained depressed, CBF decreased to 40% of control, and high-energy substrates failed to normalize. In keeping with the depression of oxidative metabolism and blood flow, neurological function and the EEG remained abnormal even after 1 h of glucose infusion. The findings suggest that irreversible brain injury may develop within the first minutes of hypoglycemic coma.     

Potential hypoglycemic effects of Chlorella in streptozotocin-induced diabetic mice

Chlorella, a type of unicellular fresh water algae, has been a popular foodstuff in Japan and Taiwan. Chlorella has been shown to produce hypoglycemic effects in alloxan-induced diabetic animals. However, there are no other reports of the effects of this substance in other diabetic animal models. Here we have used streptozocin (STZ)-induced diabetic mice to study the thypoglycemic effects of Chlorella. Diabetes was induced in ICR strain mice by the i.p. injection of STZ. Vehicle-treated ICR mice were used as normal control animals and glibenclamide was used as a positive drug control. The effects of Chlorella on basal blood glucose, exogenous insulin sensitivity test and plasma insulin levels were measured. In normal mice Chlorella produced a transient hypoglycemic effect at 90 min after acute administration; whereas glibenclamide produced a more sustained hypoglycemic effect between 90 min and 180 min after acute administration. Chlorella did not affect the basal blood glucose level in STZ mice. However, Chlorella enhanced and prolonged the hypoglycemic effects of injected insulin in STZ mice for a further 60 min compared to the normal vehicle-treated group. Plasma insulin levels were increased in normal mice after treatment with glibenclamide, whereas Chlorella had no such effect. The current results indicate that Chlorella enhances the hypoglycemic effects of exogenous insulin at a dose which does not produce hypoglycemia in STZ mice, suggesting that insulin sensitivity is increased in these mice.     

Influence of chronic respiratory acid-base disorders on acute CO2 titration curve

We have recently shown that background presence of chronic metabolic acid-base disorder markedly alters in vivo acute CO2 titration curve. These studies were carried out to assess the influence of chronic respiratory acid-base disorders on response to acute hypercapnia and to explore whether the chronic level of plasma pH is the factor responsible for alterations in the CO2 titration curve. We compared whole-body responses to acute hypercapnia of dogs with preexisting chronic respiratory alkalosis (n = 8) with that of normal animals (n = 4) and animals with chronic respiratory acidosis (n = 13). Chronic respiratory alkalosis and acidosis, as well as the acute CO2 titrations, were produced in unanesthetized dogs within a large environmental chamber. For comparison with our data on chronic metabolic acidosis and alkalosis, plasma bicarbonate levels, which are secondarily altered in chronic respiratory acid-base disorders, were used as an index of chronic acid-base status of the animals. Results indicate that, as with chronic metabolic acid-base disorders, a larger increment in plasma bicarbonate occurs during acute hypercapnia when steady-state plasma bicarbonate is low (respiratory alkalosis) than when it is high (respiratory acidosis). Yet, in further analogy with the metabolic studies, plasma hydrogen ion concentration is better defended at higher plasma bicarbonate levels in accordance with mathematical relationships defined by the Henderson-Hasselbalch equation. Combined results demonstrate that the influence of chronic acid-base status on whole-body response to acute hypercapnia is independent of initial plasma pH.(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in muscle mRNAs for hexokinase, phosphofructokinase-1 and glycogen synthase in acute and persistent hypoglycemia induced by tolbutamide in chickens

To elucidate the specificity of glucose metabolism in chicken skeletal muscle, changes in mRNA levels of hexokinase I (HKI), hexokinase II (HKII), phosphofructokinase-1 (PFK-1) and glycogen synthase (GS) were characterized in acute and persistent hypoglycemia induced by tolbutamide administration. In acute hypoglycemia, induced by a single dose of tolbutamide (100 mg/kg body mass), HKII, PFK-1 and GS mRNA levels remained unchanged; however, levels of HKI mRNA and glucose transporter 1 (GLUT1) were significantly increased 4 h after administration. In persistent hypoglycemia, induced by sequential administration of tolbutamide (100 mg/kg body mass) 3 times a day for 5 days, GS mRNA was significantly increased at day 5, while HKI, HKII and PFK-1 mRNA levels remained unchanged. These results suggest that HKI is responsible for glucose transport into skeletal muscle in acute hypoglycemia and that glucose preferentially enters the glycogenic pathway before the glycolytic pathway in persistently hypoglycemic chickens.