Counterregulatory Hormone Responses Research Articles

Impaired overnight counterregulatory hormone responses to spontaneous hypoglycemia in children with type 1 diabetes.

To assess the changes in counterregulatory hormones overnight after an afternoon of structured exercise or sedentary activity in children with type 1 diabetes mellitus (T1DM), the Diabetes Research in Children Network (DirecNet) studied 50 children (10 to <18 yr) with T1DM in five clinical research centers on two separate days (with and without an afternoon exercise session) using a crossover design. Glucose, epinephrine, norepinephrine, cortisol, growth hormone (GH), and glucagon concentrations were measured hourly overnight. Nocturnal hypoglycemia [plasma glucose concentrations < or =70 mg/dL (3.9 mmol/L)] occurred more frequently on the nights following exercise (56 vs. 36%; p = 0.008). Mean hourly concentrations of most hormones did not differ between sedentary or exercise nights or between nights with or without hypoglycemia. Spontaneous nocturnal hypoglycemia only stimulated small increases in plasma epinephrine and GH concentrations and failed to cause a rise in norepinephrine, cortisol, or glucagon levels in comparison with values during the hour before or after hypoglycemia or other times during those same nights. Counterregulatory hormone responses to spontaneous nocturnal hypoglycemia were markedly decreased regardless of whether there was antecedent afternoon exercise in children with T1DM. Sleep-induced impairments in counterregulatory hormone responses likely contribute to the increased risk of hypoglycemia during the entire overnight period in youth with T1DM.

Portal vein hypoglycemia is essential for full induction of hypoglycemia-associated autonomic failure with slow-onset hypoglycemia

Antecedent hypoglycemia leads to impaired counterregulation and hypoglycemic unawareness. To ascertain whether antecedent portal vein hypoglycemia impairs portal vein glucose sensing, thereby inducing counterregulatory failure, we compared the effects of antecedent hypoglycemia, with and without normalization of portal vein glycemia, upon the counterregulatory response to subsequent hypoglycemia. Male Wistar rats were chronically cannulated in the carotid artery (sampling), jugular vein (glucose and insulin infusion), and mesenteric vein (glucose infusion). On day 1, the following three distinct antecedent protocols were employed: 1) HYPO-HYPO: systemic hypoglycemia (2.52 +/- 0.11 mM); 2) HYPO-EUG: systemic hypoglycemia (2.70 +/- 0.03 mM) with normalization of portal vein glycemia (portal vein glucose = 5.86 +/- 0.10 mM); and 3) EUG-EUG: systemic euglycemia (6.33 +/- 0.31 mM). On day 2, all groups underwent a hyperinsulinemic-hypoglycemic clamp in which the fall in glycemia was controlled so as to reach the nadir (2.34 +/- 0.04 mM) by minute 75. Counterregulatory hormone responses were measured at basal (-30 and 0) and during hypoglycemia (60-105 min). Compared with EUG-EUG, antecedent hypoglycemia (HYPO-HYPO) significantly blunted the peak epinephrine (10.44 +/- 1.35 vs. 15.75 +/- 1.33 nM: P = 0.01) and glucagon (341 +/- 16 vs. 597 +/- 82 pg/ml: P = 0.03) responses to next-day hypoglycemia. Normalization of portal glycemia during systemic hypoglycemia on day 1 (HYPO-EUG) prevented blunting of the peak epinephrine (15.59 +/- 1.43 vs. 15.75 +/- 1.33 nM: P = 0.94) and glucagon (523 +/- 169 vs. 597 +/- 82 pg/ml: P = 0.66) responses to day 2 hypoglycemia. Consistent with hormonal responses, the glucose infusion rate during day 2 hypoglycemia was substantially elevated in HYPO-HYPO (74 +/- 12 vs. 49 +/- 4 micromol x kg(-1) x min(-1); P = 0.03) but not HYPO-EUG (39 +/- 7 vs. 49 +/- 4 micromol x kg(-1) x min(-1): P = 0.36). Antecedent hypoglycemia local to the portal vein is required for the full induction of hypoglycemia-associated counterregulatory failure with slow-onset hypoglycemia.

Type 1 corticotropin-releasing factor receptors in the ventromedial hypothalamus promote hypoglycemia-induced hormonal counterregulation

Type 2 corticotropin-releasing factor (CRF) receptors (CRFR2) within the ventromedial hypothalamus (VMH), a key glucose-sensing region, play a major role in regulating the hormonal counterregulatory responses (CRRs) to acute hypoglycemia. The VMH expresses both subtypes of CRF receptors, CRFR1 and CRFR2. The objective of this study was to examine the role of the CRFR1 receptor in the VMH in the regulation of the CRR to acute hypoglycemia. To compare the hormonal CRR to hypoglycemia, awake and unrestrained Sprague-Dawley rats were bilaterally microinjected to the VMH with either 1) aECF, 2) CRF (1 pmol/side), 3) CRFR1 antagonist Antalarmin (500 pmol/side), or 4) CRF + Antalarmin prior to undergoing a hyperinsulinemic hypoglycemic (2.8 mM) clamp. A second series of studies also incorporated an infusion of [(3)H]glucose to allow the calculation of glucose dynamics. In addition the effect of CRFR1 antagonism in the paraventricular nucleus (PVN) was studied. Activation of VMH CRFR1 increased, whereas inhibition of CRFR1 suppressed hypoglycemia-induced CRRs. Inhibition of VMH CRFR1 also increased peripheral glucose utilization and reduced endogenous glucose production during hypoglycemia, whereas VMH CRF reduced peripheral glucose utilization. In contrast CRFR1 inhibition in the PVN blunted corticosterone but not epinephrine or glucagon CRR to hypoglycemia. In contrast to CRFR2 activation, CRFR1 activation within the VMH amplifies CRRs to acute hypoglycemia. The balance between these two opposing CRFRs in this key glucose-sensing region may play an important role in determining the magnitude of CRRs to acute hypoglycemia.

Responses to acute exercise in type 2 diabetes, with an emphasis on metabolism and interaction with oral hypoglycemic agents and food intake

In people with type 1 diabetes mellitis (DM), insulin administration, food intake, and exercise have to be carefully matched to avoid either hypo- or hyperglycemia. People with type 2 DM have some insulin secretion, which changes with needs. Accordingly, during exercise, these people do not run the same metabolic risks as people with type 1 DM. However, a contraction-mediated increase in glucose clearance in muscle is intact in type 2 DM. Therefore, in the postabsorptive state in diet-treated type 2 DM, a marked reduction in hyperglycemia can occur during prolonged moderate exercise. Sulfonylurea drugs augment the rate of decline in plasma glucose, because stimulation of insulin secretion reduces hepatic glucose production. After abstention from sulfonylurea for 5 days, the rate of decrease in plasma glucose with exercise is also enhanced, but from a higher glucose level. In the postabsorptive state, brief vigourous exercise elicits an increase in plasma glucose concentration, reflecting an exaggerated counterregulatory hormone response and glucose production. Moreover, insulin sensitivity is reduced in the early postexercise period. In the postprandial state, both prolonged moderate exercise and intermittent high-intensity exercise markedly decrease meal-induced increases in glucose, insulin, and C-peptide concentrations, whereas glucose appearance in plasma is unchanged. When exercise bouts are isocaloric, responses are identical, indicating that overall energy expenditure, and not peak exercise intensity, is the major determinant of exercise-induced changes in overall glucose homeostasis and insulin secretion in type 2 DM. Neither prolonged moderate nor intermittent high-intensity exercise performed in the postprandial state influences glucose or insulin responses to a subsequent meal. Finally, in people with type 2 DM, after a high-fat meal, prolonged moderate exercise reduces the exaggerated increases in plasma concentrations of triglycerides contained in chylomicrons and very low-density lipoproteins.

Impact of the short-term, intense exercise on postprandial glycemia in type 2 diabetic patients treated with gliclazide

Background Physical activity is crucial for treatment of diabetes. However, intensive exercise brings the risk for metabolic decompensation; therefore, predicting its effect on glycemia is of great importance. Materials and Methods Fourteen type 2 diabetic patients (47.9±1.6 years; mean±S.E.M.), treated with gliclazide, and 14 healthy controls (45.1±1.0 years) were subjected to standard graded submaximal (90% HR max) exercise treadmill testing for 2 h after standardized breakfast. Blood glucose, lactate, insulin, and proinsulin concentrations were measured on fasting and during the periexercise period up to 120 min after the effort. Glucagon, growth hormone, cortisol, and catecholamines were determined up to 60 min of the recovery period. Results After exercise, glycemia decreased from the preexercise value of 11.3±1.4 to 8.0±1.1 mmol/l at 120 min ( P<.001) in the diabetic group, while in controls, it did not change significantly. Shift in glycemia during and after exercise in the diabetic group was dependent on preexercise glycemia, according to the quadratic polynomial regression model, whereas a simple negative correlation between these indices was found in the control group. Insulinemia tended to decrease from the midexercise maximum of 488±116 to 261±71 pmol/l at the 120th min in diabetic patients. Neither hypoglycemia nor deficit in response of counterregulatory hormones was observed. Conclusions In the type 2 diabetic patients treated with gliclazide, short-term, intensive, submaximal exercise, performed 2 h after a meal, causes reduction of hyperglycemia during the recovery period. Preexercise glycemia was found to be a primary predictor of the shift in glycemia under the exercise, according to the polynomial regression model.

Influence of acute alcohol ingestion on the hormonal responses to modest hypoglycaemia in patients with Type 1 diabetes

To determine whether mild alcohol intoxication (45-50 mg/dl) influences counterregulatory hormone responses to moderate hypoglycaemia (2.8 mmol/l)in patients with Type 1 diabetes. Seventeen subjects (14 male, age range 21-46 years) with Type 1 diabetes underwent four hyperinsulinaemic glucose clamps: euglycaemia with placebo; euglycaemia with alcohol (0.4 g/kg); hypoglycaemia (2.8 mmol/l for 65 min)with placebo; and hypoglycaemia (2.8 mmol/l for 65 min) with alcohol (0.4 g/kg). Arterialized venous blood samples were taken for measurement of insulin and counterregulatory hormones. During hypoglycaemia, peak growth hormone concentrations were significantly lower after alcohol compared with placebo (14.3 +/- 2.9 vs.25.9 +/- 3.4 microg/l,P< 0.001) associated with reduced insulin sensitivity in both hypoglycaemia and euglycaemia studies. We found an attenuated growth hormone response to hypoglycaemia associated with mild alcohol intoxication. Although this may potentially contribute to impaired recovery of glucose after hypoglycaemia in patients with Type 1 diabetes, it appears to be offset by a reduction in insulin action.

Glycemic Thresholds for Activation of Counterregulatory Hormone and Symptom Responses in Islet Transplant Recipients

In patients with type 1 diabetes and reduced awareness of hypoglycemia, the glycemic thresholds for activation of counterregulatory hormone and symptom responses to hypoglycemia are impaired, in part due to recurrent episodes of hypoglycemia. Islet transplantation can ameliorate occurrences of hypoglycemia in these patients. The objective of the study was to determine whether the avoidance of hypoglycemia achieved through islet transplantation results in improved glycemic thresholds for counterregulatory responses. The study was conducted at a general clinical research center. Seven islet transplant recipients, six type 1 diabetic, and eight nondiabetic control subjects participated in the study. We performed a stepped hyperinsulinemic hypoglycemic clamp and, in 12 subjects, a paired hyperinsulinemic euglycemic clamp to calculate the glycemic thresholds for and magnitude of counterregulatory responses. The glycemic thresholds for all counterregulatory hormone and symptom responses in the islet transplant group were comparable with normal and higher than in the type 1 diabetes group (P < 0.01 for glucagon; P < 0.05 for epinephrine). The magnitude of the glucagon and epinephrine responses in the islet transplant group, although greater than in the type 1 diabetes group (P < 0.05 for both), remained less than normal (P < 0.01 for glucagon; P < 0.05 for epinephrine). The magnitude of GH secretion in the islet transplant group was comparable with normal and greater than in the type 1 diabetes group (P < 0.05). The glycemic thresholds for activation of counterregulatory hormone and symptom responses appear normal after islet transplantation; however, the magnitudes of the glucagon and epinephrine responses remain impaired.

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.

Role of Hypothalamic Adenosine 5′-Monophosphate-Activated Protein Kinase in the Impaired Counterregulatory Response Induced by Repetitive Neuroglucopenia

Antecedent hypoglycemia blunts counterregulatory responses that normally restore glycemia, a phenomenon known as hypoglycemia-associated autonomic failure (HAAF). The mechanisms leading to impaired counterregulatory responses are largely unknown. Hypothalamic AMP-activated protein kinase (AMPK) acts as a glucose sensor. To determine whether failure to activate AMPK could be involved in the etiology of HAAF, we developed a model of HAAF using repetitive intracerebroventricular (icv) injection of 2-deoxy-D-glucose (2DG) resulting in transient neuroglucopenia in normal rats. Ten minutes after a single icv injection of 2DG, both alpha1- and alpha2-AMPK activities were increased 30-50% in arcuate and ventromedial/dorsomedial hypothalamus but not in other hypothalamic regions, hindbrain, or cortex. Increased AMPK activity persisted in arcuate hypothalamus at 60 min after 2DG injection when serum glucagon and corticosterone levels were increased 2.5- to 3.4-fold. When 2DG was injected icv daily for 4 d, hypothalamic alpha1- and alpha2-AMPK responses were markedly blunted in arcuate hypothalamus, and alpha1-AMPK was also blunted in mediobasal hypothalamus 10 min after 2DG on d 4. Both AMPK isoforms were activated normally in arcuate hypothalamus at 60 min. Counterregulatory hormone responses were impaired by recurrent neuroglucopenia and were partially restored by icv injection of 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside, an AMPK activator, before 2DG. Glycogen content increased 2-fold in hypothalamus after recurrent neuroglucopenia, suggesting that glycogen supercompensation could be involved in down-regulating the AMPK glucose-sensing pathway in HAAF. Thus, activation of hypothalamic AMPK may be important for the full counterregulatory hormone response to neuroglucopenia. Furthermore, impaired or delayed AMPK activation in specific hypothalamic regions may play a critical role in the etiology of HAAF.

A Pilot Study of the SPRINT Protocol for Tight Glycemic Control in Critically Ill Patients

Stress-induced hyperglycemia is prevalent in critical care, even in patients with no history of diabetes. Increased counter-regulatory hormone response increases gluconeogenesis and effective insulin resistance, which can be exacerbated by drug therapy. Control of blood glucose levels to the 4.0-6.1 mmol/L range has been shown to reduce mortality and improve clinical outcomes. The Specialized Relative Insulin and Nutrition Tables (SPRINT) protocol is a simple alternative intensive care unit protocol for modulating insulin and nutritional input to gain tight blood glucose control in the 4.0-6.1 mmol/L target band. The look-up tables, implemented in a wheel-based format, are used by nurses to determine glycemic control actions based on hourly or 2-hourly blood glucose measurements and nutrition and insulin administration rates. An 11 patient pilot study was conducted comprising 2,152 hours of blood glucose level control using the SPRINT protocol. The patient cohort average Acute Physiology and Chronic Health Evaluation II score was 22, which was higher than previous intensive insulin clinical studies. Overall, 64% of measurements were in the 4.0-6.1 mmol/L band, 89% in the 4.0-7.0 mmol/L band, and 96% of all measurements in the 4.0-7.75 mmol/L band. The average value was 5.8 +/- 0.9 mmol/L. Only 1.4% of all measurements were below 4 mmol/L, with a minimum of 3.2 mmol/L. The maximum value recorded was 11.8 mmol/L. Control of blood glucose level was achieved using a protocol implemented by the nursing staff without the need for physician intervention or interpretation, where control is defined as maximizing time within a desired band. The results led to a high level of support for the SPRINT protocol among clinical staff and acceptance of the frequent measurement requirement for effective control. The ease-of-use of the protocol resulted in minimal noncompliance by clinical staff.

Absence of Sexual Dimorphism in the Symptomatic Responses to Hypoglycemia in Adults With and Without Type 1 Diabetes

Insulin-induced hypoglycemia provokes counterregulatory hormonal responses, the magnitude of which is lower in women with and without type 1 diabetes than in their male counterparts (1–5), although the glycemic thresholds at which these responses are triggered are similar in both sexes (6,7). In nondiabetic adults and people with type 1 diabetes, antecedent hypoglycemia and exercise had less effect on the magnitude of the counterregulatory hormonal responses in women than in men (8,9). It has therefore been suggested that exposure to recurrent episodes of hypoglycemia could abolish the difference in counterregulatory responses between the sexes, explaining the absence of a difference in the overall frequency of severe hypoglycemia observed in the Diabetes Control and Complications Trial (10). Detection of the symptoms of hypoglycemia alerts the person with diabetes to the decline in blood glucose, prompting corrective action to be taken before the effects of neuroglycopenia become disabling. Symptoms of hypoglycemia are generated as part of the established hierarchy of responses (11,12) and are idiosyncratic and age specific (13). Sex differences have not been reported, but in small studies with few subjects, a putative difference may not be discernible (1,14). The most common hypoglycemia symptoms have been classified into subgroups in physiological studies (15,16) and by statistical methodology (17–20) using factor analysis. The subgroups include autonomic symptoms, such as hunger, pounding heart, …

Activation of AMP-Activated Protein Kinase Within the Ventromedial Hypothalamus Amplifies Counterregulatory Hormone Responses in Rats With Defective Counterregulation

Defective counterregulatory responses (CRRs) to hypoglycemia are associated with a marked increase in the risk of severe hypoglycemia. The mechanisms leading to the development of defective CRRs remain largely unknown, although they are associated with antecedent hypoglycemia. Activation of AMP-activated protein kinase (AMPK) in the ventromedial hypothalamus (VMH) amplifies the counterregulatory increase in glucose production during acute hypoglycemia. To examine whether activation of AMPK in the VMH restores defective CRR, controlled hypoglycemia ( approximately 2.8 mmol/l) was induced in a group of 24 Sprague-Dawley rats, all of which had undergone a 3-day model of recurrent hypoglycemia before the clamp study. Before the acute study, rats were microinjected to the VMH with either 5-aminoimidazole-4-carboxamide (AICAR; n=12), to activate AMPK, or saline (n=12). In a subset of rats, an infusion of H(3)-glucose was additionally started to calculate glucose turnover. Stimulation of AMPK within the VMH was found to amplify hormonal CRR and increase endogenous glucose production. In addition, analysis of tissue from both whole hypothalamus and VMH showed that recurrent hypoglycemia induces an increase in the gene expression of AMPK alpha(1) and alpha(2). These findings suggest that the development of novel drugs designed to selectively activate AMPK in the VMH offer a future therapeutic potential for individuals with type 1 diabetes who have defective CRRs to hypoglycemia.

Insulinoma in Differential Diagnosis of Seizure Disorder

Back to table of contents Previous article Next article LETTERFull AccessInsulinoma in Differential Diagnosis of Seizure DisorderAlemdar Murat M.D.Iseri Pervin M.D.Komsuoglu Sezer Sener M.D.,Alemdar Murat M.D.Search for more papers by this authorIseri Pervin M.D.Search for more papers by this authorKomsuoglu Sezer Sener M.D.Search for more papers by this author,Published Online:1 Apr 2006AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail SIR: Hypoglycemia can mimic epileptic seizures, and insulinoma is one of the rarest causes of it. The authors report on a patient with hypoglycemic spells caused by insulinoma misdiagnosed as intractable epilepsy. The medical history of the case highlights the importance of careful management in the seizures of adulthood, especially in those that are atypical and refractory to pharmacotherapy. Case ReportA 42-year-old man was referred to our clinic for evaluation of recurrent seizures which had begun to occur 10 months before and were usually seen in the early morning or during tiring work. He had been diagnosed with epilepsy and anxiety disorder by a neurologist, and phenytoin and alprozolam treatment had been prescribed. The frequency of attacks had increased up to four times a week in the previous 3 months. He was referred to our clinic after these complaints. Also, he had no response to carbamazepine and levetiracetam treatment, and the electroencephalogram (EEG) performed shortly after an episode showed diffuse rhythmic theta activity.The typical attack was seen on the first morning of hospitalization after a fast of 10 hours. It began with fatigue and psychomotor slowing. Some bizarre behaviors, like crying, “I will die” and moving his extremities aimlessly were observed, followed by loss of consciousness. The peripheral glucose level was 30 mg/dl. Upon administration of intravenous glucose solution, he became alert and all symptoms subsided after a few minutes. The blood sample sent for investigations prior to therapy also revealed the low plasma glucose (21 mg/dl) and high circulating insulin level (15 μU/ml). The attacks did not recur with continuous intravenous glucose administration.An abdominal MRI revealed a 17 mm round nodular mass located over the pancreatic tail. Surgical removal of the tumor resulted in complete resolution of the symptoms and reversion of the insulin and glucose levels back to normal levels. The microscopic evaluation of removed material also confirmed the diagnosis of insulinoma.Comment Insulinomas are rare neoplasms recognized by an inappropriately high circulating insulin level, for the ambient blood glucose concentration. The most common neurological feature at presentation is confusion. As the disorder evolves, coma, motor deficits, or convulsions begin to occur. 1 Unless there is the presence of localized abnormalities in the cerebral circulation, low glucose level affects all cerebral neurons, resulting in a generalized dysfunction which may present as diffuse slow activity in EEG and lead the clinician to prescribe antiepileptics, as in our case. The episodic nature of hypoglycemia in insulinoma also causes the symptoms to fluctuate, and delays the diagnosis. Confusion or bizarre behavior which could be misdiagnosed as an epileptic disorder are much more common (approximately 25%), although nearly six percent of the hypoglycemic cases present with seizures. 2 Hypoglycemia itself can also induce unawareness of the autonomic and neuroglycopenic symptoms and decrease the counterregulatory hormonal responses in insulinoma. 3 So, the unawareness of autonomic symptoms might play a critical role in misinterpretation, as in our case. Once diagnosed as a refractory epileptic disorder, a significant proportion of patients receive aggressive and escalating pharmacotherapy. Remembering that the metabolic causes of seizures are almost always curable, and may be fatal if untreated, this report highlights the need for careful assessment of every seizure. The critical importance of assessment of blood glucose level in patients with altered level of consciousness is again impressed. Insulinoma, though uncommon, is a potentially recognizable and treatable disease, as long as there is a high index of suspicion. It should always be considered among the diagnostic possibilities in any patient with unusual or inexplicable neurological features, including atypical seizures refractory to pharmacotherapy.Kocaeli University, Faculty of Medicine, Department of Neurology, Kocaeli, Turkey

The Role of Endocrine Counterregulation for Estimating Insulin Sensitivity from Intravenous Glucose Tolerance Tests

During insulin-modified frequently sampled iv glucose tolerance tests (IM-FSIGT), which allow assessment of insulin action, plasma glucose can markedly decrease. This study aimed to assess the counterregulatory impact of the insulin-induced fall of glucose on minimal model-derived indices of insulin sensitivity (S(I)) and glucose effectiveness. Thirteen nondiabetic volunteers (seven males, six females, aged 26 +/- 1 yr, body mass index 22.1 +/- 0.7 kg/m(2)) were studied. All participants were studied in random order during IM-FSIGT (0.3 g/kg glucose; 0.03 U/kg insulin at 20 min) and during identical conditions but with a variable glucose infusion preventing a decrease of plasma glucose concentration below euglycemia (IM-FSIGT-CLAMP). Five participants additionally underwent euglycemic-hyperinsulinemic (1 mU.kg(-1).min(-1)) clamp tests. Plasma glucose declined during IM-FSIGT to its nadir of 50 +/- 3 mg/dl at 60 min in parallel to a rise (P < 0.05 vs. basal) of plasma glucagon, cortisol, epinephrine, and GH. Glucose infusion rates of 4.6 +/- 0.5 mg.kg(-1).min(-1) between 30 and 180 min during IM-FSIGT-CLAMP prevented the decline of plasma glucose and the hypoglycemia counterregulatory hormone response. S(I) was approximately 68% lower during IM-FSIGT (3.40 +/- 0.36 vs. IM-FSIGT-CLAMP: 10.71 +/- 1.06 10(-4).min(-1) per microU/ml, P < 0.0001), whereas glucose effectiveness did not differ between both protocols (0.024 +/- 0.002 vs. 0.021 +/- 0.003 min(-1), P = NS). Compared with the euglycemic hyperinsulinemic clamp test, S(I) expressed in identical units from IM-FSIGT was approximately 66% (P < 0.001) lower but did not differ between the euglycemic hyperinsulinemic clamp test and the IM-FSIGT-CLAMP (P = NS). The transient fall of plasma glucose during IM-FSIGT results in lower estimates of S(I), which can be explained by hormonal response to hypoglycemia.

Role of Hepatic Glycogen Breakdown in Defective Counterregulation of Hypoglycemia in Intensively Treated Type 1 Diabetes

Impairment of hypoglycemic counterregulation in intensively treated type 1 diabetes has been attributed to deficits in counterregulatory hormone secretion. However, because the liver plays a critical part in recovery of plasma glucose, abnormalities in hepatic glycogen metabolism per se could also play an important role. We quantified the contribution of net hepatic glycogenolysis during insulin-induced hypoglycemia in 10 nondiabetic subjects and 7 type 1 diabetic subjects (HbA1c 6.5 +/- 0.2%) using 13C nuclear magnetic resonance spectroscopy, during 2 h of either hyperinsulinemic euglycemia (plasma glucose 92 +/- 4 mg/dl) or hypoglycemia (plasma glucose 58 +/- 3 mg/dl). In nondiabetic subjects, hypoglycemia was associated with a brisk counterregulatory hormone response (plasma epinephrine 246 +/- 38 vs. 2,785 +/- 601 pmol/l during hypoglycemia, plasma norepinephrine 1.9 +/- 0.2 vs. 2.5 +/- 0.3 nmol/l, and glucagon 38 +/- 7 vs. 92 +/- 17 pg/ml, respectively, P < 0.001 in all), and a relative increase in endogenous glucose production (EGP 0.83 +/- 0.14 mg x kg(-1) x min(-1) during euglycemia yet approximately 50% higher with hypoglycemia [1.30 +/- 0.20 mg x kg(-1) x min(-1)], P < 0.001). Net hepatic glycogen content declined progressively during hypoglycemia to 22 +/- 3% below baseline (P < 0.024). By the final 30 min of hypoglycemia, hepatic glycogen fell from 301 +/- 14 to 234 +/- 10 mmol/l (P < 0.001) and accounted for approximately 100% of EGP. In marked contrast, after an overnight fast, hepatic glycogen concentration in type 1 diabetic subjects (215 +/- 23 mmol/l) was significantly lower than in nondiabetic subjects (316 +/- 19 mmol/l, P < 0.001). Furthermore, the counterregulatory response to hypoglycemia was significantly reduced with small increments in plasma epinephrine and norepinephrine (126 +/- 22 vs. 448 +/- 16 pmol/l in hypoglycemia and 0.9 +/- 0.3 vs. 1.6 +/- 0.3 nmol/l, respectively, P < 0.05 for both) and no increase in plasma glucagon. EGP decreased during hypoglycemia with no recovery (1.3 +/- 0.5 vs. 1.2 +/- 0.3 mg x kg(-1) x min(-1) compared with euglycemia, P = NS), and hepatic glycogen concentration did not change significantly with hypoglycemia. We conclude that glycogenolysis accounts for the majority of EGP during the first 90 min of hypoglycemia in nondiabetic subjects. In intensively treated type 1 diabetes, despite some activation of counterregulation, hypoglycemia failed to stimulate hepatic glycogen breakdown or activation of EGP, factors that may contribute to the defective counterregulation seen in such patients.

Reduced exercise-associated response of the GH-IGF-I axis and catecholamines in obese children and adolescents

Obesity blunts catecholamine and growth hormone (GH) responses to exercise in adults, but the effect of obesity on these exercise-associated hormonal responses in children is unclear. Therefore, the aim of the present study was to asses the effect of childhood obesity on the counterregulatory hormonal response to acute exercise. Twenty-five obese children (Ob; body mass index > 95%), and 25 age, gender, and maturity-matched normal-weight controls (NW) participated in the study. Exercise consisted of ten 2-min bouts of constant-cycle ergometry above the anaerobic threshold, with 1-min rest intervals between each bout. Pre-, post-, and 120-min postexercise blood samples were collected for circulating components of the GH-IGF-I axis and catecholamines. There were no differences in peak exercise heart rate, serum lactate, and peak O2 uptake normalized to lean body mass between the groups. Obesity attenuated the GH response to exercise (8.9 +/- 1.1 vs. 3.4 +/- 0.7 ng/ml in NW and Ob participants, respectively; P < 0.02). No significant differences in the response to exercise were found for other components of the GH-IGF-I axis. Obesity attenuated the catecholamine response to exercise (epinephrine: 52.5 +/- 12.7 vs. 18.7 +/- 3.7 pg/ml, P < 0.02; norepinephrine: 479.5 +/- 109.9 vs. 218.0 +/- 26.0 pg/ml, P < 0.04; dopamine: 17.2 +/- 2.9 vs. 3.5 +/- 1.9 pg/ml, P < 0.006 in NW and Ob, respectively). Insulin levels were significantly higher in the obese children and dropped significantly after exercise in both groups. Despite the elevated insulin levels and the blunted counterregulatory response, none of the participants developed hypoglycemia. Childhood obesity was associated with attenuated GH and catecholamine response to acute exercise. These abnormalities were compensated for, so that exercise was not associated with hypoglycemia, despite increased insulin levels in obese children.

Activation of ATP-Sensitive K+ Channels in the Ventromedial Hypothalamus Amplifies Counterregulatory Hormone Responses to Hypoglycemia in Normal and Recurrently Hypoglycemic Rats

The mechanism(s) by which glucosensing neurons detect fluctuations in glucose remains largely unknown. In the pancreatic beta-cell, ATP-sensitive K+ channels (K ATP channels) play a key role in glucosensing by providing a link between neuronal metabolism and membrane potential. The present study was designed to determine in vivo whether the pharmacological opening of ventromedial hypothalamic K ATP channels during systemic hypoglycemia would amplify hormonal counterregulatory responses in normal rats and those with defective counterregulation arising from prior recurrent hypoglycemia. Controlled hypoglycemia (approximately 2.8 mmol/l) was induced in vivo using a hyperinsulinemic (20 mU x kg(-1) x min(-1)) glucose clamp technique in unrestrained, overnight-fasted, chronically catheterized Sprague-Dawley rats. Immediately before the induction of hypoglycemia, the rats received bilateral ventromedial hypothalamic microinjections of either the potassium channel openers (KCOs) diazoxide and NN414 or their respective controls. In normal rats, both KCOs amplified epinephrine and glucagon counterregulatory responses to hypoglycemia. Moreover, diazoxide also amplified the counterregulatory responses in a rat model of defective hormonal counterregulation. Taken together, our data suggest that the K ATP channel plays a key role in vivo within glucosensing neurons in the ventromedial hypothalamus in the detection of incipient hypoglycemia and the initiation of protective counterregulatory responses. We also conclude that KCOs may offer a future potential therapeutic option for individuals with insulin-treated diabetes who develop defective counterregulation.

Geriatric Patient With Repetitive Hypoglycaemic Episodes

Hypoglycaemia is one of the significant hospitalization reasons in elderly patients with diabetes mellitus. Concerns should increase in admission of such a case in the emergency room owing to a number of associated disorders which may contribute to the undesired consequences. An eighty-year-old diabetic woman who was on glimepiride therapy was brought to the emergency unit because of repeated episodes of hypoglycaemia. She was having Alzheimer’s disease leading to forget the usual dose she was receiving that also gives rise to double the pill together with skipping the snacks. Age related changes in pharmacokinetics and the potential for adverse effects and drug interactions due to polypharmacy leading to interactions and less adherence to receive the right dose at the right time should also be considered when choosing appropriate pharmacological therapy. Geriatric patients require special considerations related to delayed response of counter-regulatory hormones to hypoglycaemia and associated conditions must be taken into consideration for a successful management program.

Hypoglycemia-induced noradrenergic activation in the VMH is a result of decreased ambient glucose

During insulin-induced hypoglycemia, there is an increase in extracellular norepinephrine (NE) in the ventromedial hypothalamus (VMH). This brain area is known to play an important role in integrated hormonal and behavioral responses to systemic hypoglycemia. Selective glucoprivation restricted to the VMH is both necessary and sufficient to initiate secretion of counterregulatory hormones. The present study was designed to investigate whether increased release of NE in the VMH depends on detection of glucoprivation localized in this area. In awake, chronically catheterized male Sprague-Dawley rats, extracellular NE in the VMH was monitored using 1-mm microdialysis probes perfused with Krebs Ringer buffer (KRB) or KRB + 100 mM d-glucose (d-Glc). During insulin-induced hypoglycemia (glycemic nadir approximately 2.4 mM) extracellular NE was increased to >160% of baseline (P < 0.01) only in the KRB + insulin group. There was no increase in NE from baseline when glucose was added to the perfusate to maintain euglycemia at the periprobe environment. The sympathoadrenal response to hypoglycemia, present in the KRB + insulin group, was attenuated in the d-Glc + insulin group. The present results confirm that noradrenergic activation in the VMH during systemic hypoglycemia depends on detection of glucoprivation locally in this area. These data provide additional support for the importance of increased noradrenergic activity in the VMH in the counterregulatory hormonal responses to hypoglycemia.

Serum Glucagon Counterregulatory Hormonal Response to Hypoglycemia Is Blunted in Congenital Hyperinsulinism

The mechanisms involved in the release of glucagon in response to hypoglycemia are unclear. Proposed mechanisms include the activation of the autonomic nervous system via glucose-sensing neurons in the central nervous system, via the regulation of glucagon secretion by intra-islet insulin and zinc concentrations, or via direct ionic control, all mechanisms that involve high-affinity sulfonylurea receptor/inwardly rectifying potassium channel-type ATP-sensitive K(+) channels. Patients with congenital hyperinsulinism provide a unique physiological model to understand glucagon regulation. In this study, we compare serum glucagon responses to hyperinsulinemic hypoglycemia versus nonhyperinsulinemic hypoglycemia. In the patient group (n = 20), the mean serum glucagon value during hyperinsulinemic hypoglycemia was 17.6 +/- 5.7 ng/l compared with 59.4 +/- 7.8 ng/l in the control group (n = 15) with nonhyperinsulinemic hypoglycemia (P < 0.01). There was no difference between the serum glucagon responses in children with diffuse, focal, and diazoxide-responsive forms of hyperinsulinism. The mean serum epinephrine and norepinephrine concentrations in the hyperinsulinemic group were 2,779 +/- 431 pmol/l and 2.9 +/- 0.7 nmol/l and appropriately rose despite the blunted glucagon response. In conclusion, the loss of ATP-sensitive K(+) channels and or elevated intraislet insulin cannot explain the blunted glucagon release in all patients with congenital hyperinsulinism. Other possible mechanisms such as the suppressive effect of prolonged hyperinsulinemia on alpha-cell secretion should be considered.