Counterregulatory Hormone Responses Research Articles

Erythropoietin and vascular endothelial growth factor as risk markers for severe hypoglycaemia in type 1 diabetes

Circulating erythropoietin (EPO) and vascular endothelial growth factor (VEGF) increase during hypoglycaemia and may represent protective hormonal counter-regulatory responses. We tested the hypothesis that low levels of EPO and VEGF are associated with a higher frequency of severe hypoglycaemia in a cohort of patients with type 1 diabetes. Prospective observational follow-up study. Totally 219 patients with type 1 diabetes (41% females, age 46+/-13 years (mean+/-s.d.), duration of diabetes 21+/-12 years, and HbAlc 8.5+/-1.1%) were followed in a 1-year observational study. Plasma EPO and serum VEGF levels were measured at baseline with ELISA. Events of severe hypoglycaemia defined by third party assistance were recorded and validated in telephone interviews within 24 h. Totally 235 episodes of severe hypoglycaemia (1.1 episodes per patient-year) were reported by 82 patients (37%). At baseline, plasma EPO was 8.6 (3.1-34.3) U/l (median (range)), and serum VEGF was 52.2 (6.6-337) pg/ml. The levels of EPO and VEGF were not associated with frequency of severe and mild hypoglycaemia. The levels of EPO were not associated with age, sex, duration of diabetes, body mass index, HbAlc, C-peptide level or hypoglycaemia awareness status. The levels of VEGF were positively associated with age and female sex. Although several studies suggest that VEGF and EPO may affect brain function during hypoglycaemia, this study does not support random VEGF or EPO levels to determine future risk of severe hypoglycaemia in people with type 1 diabetes.

Blunted Counterregulatory Hormone Responses to Hypoglycemia in Young Children and Adolescents With Well-Controlled Type 1 Diabetes

In adults with insulin-treated diabetes, hypoglycemia-associated autonomic failure (HAAF) is described as a syndrome that includes counterregulatory hormonal deficiencies and impaired symptomatic awareness in response to severe hypoglycemia (1). It is thought to result from failure of the central autonomic response to acute neuroglycopenia and is associated with recurrent exposure to hypoglycemia and increasing duration of diabetes. It is not known whether this syndrome occurs in children with type 1 diabetes, but the Diabetes Research in Children Network (DirecNet) Study Group has claimed that HAAF was present in at least a third of their participants with type 1 diabetes (2). Examination of the study design and methodology raises …

Blunted Counterregulatory Hormone Responses to Hypoglycemia in Young Children and Adolescents With Well-Controlled Type 1 Diabetes

We thank Graveling et al. (1) for their thoughtful comments regarding our article (2). In their letter, they argue that our conclusion was not supported by the study data because the achieved level of hypoglycemia was not adequate. They point out that the mean nadir plasma glucose level in our subjects was ∼60 mg/dl, whereas plasma glucose concentrations <60 mg/dl are often required to elicit …

Leptin and ghrelin levels in humans to physical inactivity induced by simulated microgravity

The aim of this study was to investigate the consequences of 20 days of physical inactivity induced by simulated microgravity using head‐down bed rest (HDBR) at −6° on leptin, ghrelin and counterregulatory hormone response. Eight male volunteers were subjected to HDBR for 20 days. Variables measured before, during and after HDBR included plasma cortisol, insulin, glucose, leptin, ghrelin, thyroid stimulating hormone (TSH), free thyroxine (fT4) free triiodothyronine (fT3). No changes in the ghrelin and leptin concentrations were observed during HDBR. The glucose concentration decreased significantly at the 20th day of HDBR compared to pre‐ value (day 0) of HDBR (87.6 ± 2.0 vs. 93 ± 1.6 mg/dl). Significant correlation was observed between glucose and leptin concentration. The results provide the first evidence that 20 days of HDBR is not associated with alteration in ghrelin concentration. Leptin, insulin, cortisol, concentration was not different during 20 days of HDBR.

Radix astragali (Huangqi) as a Treatment for Defective Hypoglycemia Counterregulation in Diabetes

Radix astragali is a herbal remedy used in China to treat patients with diabetes exposed to repeated episodes of hypoglycemia. The physiological basis or validity of this approach is not clear. In the present study, we examine the effect of pre-treatment with Radix astragali on hormonal counterregulatory responses to hypoglycemia in normal male Sprague-Dawley rats. Four groups of rodents were studied. In two of these groups, rodents were pre-treated for 3 days with either intravenous Radix astragali or control solution and, subsequently, while awake and unrestrained, underwent an in vivo hyperinsulinemic hypoglycemic (50 mg/dl) clamp study. The rodents in other two groups were pre-treated for 7 days with either intravenous Radix astragali or control solution. In addition, for the last 3-days of their treatment, the rats were subjected to a once-daily episode of insulin-induced hypoglycemia. Upon completion of this protocol, each rat underwent a controlled in vivo hyperinsulinemic hypoglycemic (50 mg/dl) clamp study. Radix astragali was shown to amplify the glucose counterregulatory response to hypoglycemia in both untreated and recurrently hypoglycemic rats. Immunocytochemistry studies suggested this might reflect increased neural activation in two key central glucose-sensing regions, the paraventricular hypothalamus and the nucleus tractus solitarius. Based on these rodent studies, we conclude that Radix astragali pre-treatment can amplify the counterregulatory response to hypoglycemia through a mechanism that may involve the central glucose-sensing regions. Future studies to examine the potential therapeutic benefit of Radix astragali in rodent models of type 1 diabetes are warranted.

Exercise induced hyperglycaemia in the absence of diabetes

Exercise induced hyperglycaemia in the absence of diabetes

Insulin detemir causes increased symptom awareness during hypoglycaemia compared to human insulin

The long-acting insulin analogue detemir (Levemir) has structural and physicochemical properties which differ from human insulin. The aim of the present study was to test whether this leads to altered hormone and symptom response during hypoglycaemia. 12 healthy subjects [6f/6m, age 32 +/- 6 years (mean +/- s.d.), body mass index (BMI) 24.2 +/- 2.5 kg/m(2)] underwent a 200-min stepwise hypoglycaemic clamp (45 min steps of 4.4, 3.7, 3.0 and 2.3 mmol/l) with either detemir or human insulin in random order. A bolus of detemir (660 mU/kg) or human insulin (60 mU/kg) was given before insulin was infused at a rate of 5 (detemir) or 2 (human insulin) mU/kg/min. Blood was drawn and a semi-quantitative symptom questionnaire was administered before and after each plateau of the hypoglycaemic clamp. Cognitive function was assessed during each step. Blood glucose levels and glucose infusion rates were comparable with detemir and human insulin. The total symptom score was higher with detemir during the 3 and 2.3 mmol glucose step compared to human insulin (p = 0.048). Especially sweating was increased with detemir (p = 0.02) with an earlier and faster increase during the clamp (interaction insulin x time: p = 0.04). No significant differences between detemir and human insulin in cortisol, norepinephrine, epinephrine, glucagon, growth hormone, lactate or free fatty acid (FFA) levels during hypoglycaemia were observed, and there were no significant differences in cognitive function tests. Insulin detemir increased symptom awareness during hypoglycaemia compared to human insulin in healthy individuals, whereas counter-regulatory hormone response and cognitive function were unaltered.

Blunted Counterregulatory Hormone Responses to Hypoglycemia in Young Children and Adolescents With Well-Controlled Type 1 Diabetes

OBJECTIVEHypoglycemia in young children with type 1 diabetes is an acute complication of intensive insulin therapy and is commonly observed in the absence of signs or symptoms. The effect of intensive treatment and patient age on sympathoadrenal responses has not been established in youth with type 1 diabetes because of difficulties in testing procedures.RESEARCH DESIGN AND METHODSWe developed a standardized inpatient continuous subcutaneous insulin infusion protocol to produce a progressive fall in plasma glucose concentrations in insulin pump–treated patients. Plasma glucose and counterregulatory hormone concentrations were measured in 14 young children (3 to <8 years, A1C 7.7 ± 0.6%) vs. 14 adolescents (12 to <18 years, A1C 7.6 ± 0.8%).RESULTSPlasma glucose decreased to similar nadir concentrations in the two groups. Four young children and four adolescents never had an epinephrine response. In the four young children and five adolescents who had a modest epinephrine response, this only occurred when plasma glucose fell to <60 mg/dl. In evaluating symptom scores, 29% of parents of young children felt that their child looked hypoglycemic, even at the lowest plasma glucose concentrations. Adolescents were better able to detect symptoms of hypoglycemia. In comparison with our data, epinephrine response to hypoglycemia in 14 nondiabetic adolescents studied at the Children's Hospital of Pittsburgh was higher.CONCLUSIONSThese data suggest that even young children and adolescents with type 1 diabetes are prone to develop hypoglycemia-associated autonomic failure regardless of duration. Whether these abnormalities can be reversed using continuous glucose monitoring and closed-loop insulin delivery systems awaits further study.

Comparing hormonal and symptomatic responses to experimental hypoglycaemia in insulin‐ and sulphonylurea‐treated Type 2 diabetes

Patients with diabetes rely on symptoms to identify hypoglycaemia. Previous data suggest patients with Type 2 diabetes develop greater symptomatic and hormonal responses to hypoglycaemia at higher glucose concentrations than non-diabetic controls and these responses are lowered by insulin treatment. It is unclear if this is as a result of insulin therapy itself or improved glucose control. We compared physiological responses to hypoglycaemia in patients with Type 2 diabetes patients treated with sulphonylureas (SUs) or insulin (INS) with non-diabetic controls (CON). Stepped hyperinsulinaemic hypoglycaemic clamps were performed on 20 subjects with Type 2 diabetes, 10 SU-treated and 10 treated with twice-daily premixed insulin, and 10 age- and weight-matched non-diabetic controls. Diabetic subjects were matched for diabetes duration, glycated haemoglobin (HbA(1c)) and hypoglycaemia experience. We measured symptoms, counterregulatory hormones and cognitive function at glucose plateaux of 5, 4, 3.5, 3 and 2.5 mmol/l. Symptomatic responses to hypoglycaemia occurred at higher blood glucose concentrations in SU-treated than INS-treated patients [3.5 (0.4) vs. 2.6 (0.5) mmol/l SU vs. INS; P = 0.001] or controls [SU vs. CON 3.5 (0.4) vs. 3.0 (0.6) mmol/l; P = 0.05]. They also had a greater increase in symptom scores at hypoglycaemia [13.6 (11.3) vs. 3.6 (6.1) vs. 5.1 (4.3) SU vs. INS vs. CON; P = 0.017]. There were no significant differences in counterregulatory hormone responses or impairment of cognitive function among groups. Sulphonylurea-treated subjects are more symptomatic of hypoglycaemia at a higher glucose level than insulin-treated subjects. This may protect them from severe hypoglycaemia but hinder attainment of glycaemic goals.

Changes of cognition and regional cerebral activity during acute hypoglycemia in normal subjects: A H215O positron emission tomographic study

Blurred vision and cognitive difficulties are prominent symptoms during acute insulin-induced hypoglycemia. Our hypothesis was that changes in cerebral activity reflect these symptoms. Positron emission tomography (PET) with oxygen-15-labelled water was used to measure relative changes in regional cerebral blood flow (rCBF) as a marker of cerebral activity. Hypoglycemia was induced by intravenous insulin infusion in 19 healthy men performing two different cognitive tasks of varying complexity. The hypoglycemic stimulus [plasma glucose 2.2 mmol/liter (0.4)] produced a significant hormonal counterregulatory response. During the low cognitive load, rCBF decreased in response to hypoglycemia in a large bilateral area in the posterior part of the temporal lobe, and rCBF increased bilaterally in the anterior cingulate gyrus, the right frontal gyrus, the fusiform gyrus, thalamus, and the left inferior part of the frontal gyrus. During the high cognitive load, rCBF decreased bilaterally in a large region in the posterior part of the temporal gyrus and increased in the left and right anterior cingulate gyrus, left and right frontal gyrus, right parahippocampal and lingual gyrus, and left superior temporal gyrus. Visual impairment during hypoglycemia was associated with deactivation in the ventral visual stream. The anterior cingulate gyrus was activated during hypoglycemia in a load-dependent manner. Areas on the frontal convexity were differentially activated in response to the cognitive load during hypoglycemia. Our findings suggest that hypoglycemia induces changes in sensory processing in a cognition-independent manner, whereas activation of areas of higher order functions is influenced by cognitive load as well as hypoglycemia.

Glucose Counterregulatory Hormone Response During Hypoglycemia due to Endogenous Hyperinsulinemia

Background: In patients with hypoglycemia due to endogenous hyperinsulinemia such as insulinoma or insulin autoimmune syndrome, little is known about the counterregulatory hormone response to spontaneous hypoglycemia. We therefore compared hormone responses during spontaneous hypoglycemia due to endogenous hyperinsulinemia with those at the end of a 72-hour fast. Methods: We measured glucagon, epinephrine, cortisol, and growth hormone responses during spontaneous hypoglycemia in 8 patients with insulinoma and 18 patients with insulin autoimmune syndrome. We also assessed these responses in 13 normal control subjects who underwent a 72-hour fast. Results: In patients with insulinoma (median serum glucose level, 35.0 mg/dL), plasma glucagon levels (median, 42.9 vs. 76.2 pg/mL, respectively; P < 0.05) were lower than those in control subjects (serum glucose level, 62.5 mg/dL), whereas, there were no statistically significant differences in the other hormone responses between the two groups. In contrast, in the patients with insulin autoimmune syndrome (median serum glucose level, 34.5 mg/dL), plasma glucagon levels (median, 73.7 vs. 76.2 pg/mL, respectively) were lower than those in the control subjects, but there was no statistically significant difference between the two groups. There were no statistically significant differences in counterregulatory hormone responses during spontaneous hypoglycemia between patients with insulinoma and patients with insulin autoimmune syndrome. Conclusion: Our results suggest that defective glucagon secretion in patients with insulinoma rather than insulin autoimmune syndrome may contribute to hypoglycemia in addition to hyperinsulinemia. (J Korean

Glucose Counterregulatory Hormone Response During Hypoglycemia due to Endogenous Hyperinsulinemia

162 저혈당은 증상이 발현되는 시간에 따라서 공복 저혈당과 식후(반응성) 저혈당으로 분류가 되며 공복 저혈당의 원인으 로는 당뇨병 치료에 쓰이는 인슐린, 경구용 혈당강하제 등의 사용과 관련되어 흔하게 나타난다. 인슐린 길항호르몬인 성 장호르몬, 부신호르몬 등 부족과 관련된 저혈당, 그리고 음 주 후 발생되는 저혈당 등도 공복 저혈당의 빈번한 원인을 차지하고 있다. 한편 위의 원인들 외에 내인성 고인슐린혈증이 공복 저혈 당의 원인이 되기도 하는데 그 대표적인 질환들이 인슐린종 (insulinoma)과 인슐린자가면역 증후군(insulin autoimmune syndrome, 이하 IAS)이며 발생 빈도는 다른 공복 저혈당의 원인질환들에 비해 매우 드물다. IAS는 인슐린을 투여 받은 병력이 없는 환자에게서 인슐린자가항체가 나타나며 혈중 인슐린이 상승되어 있고 공복 저혈당을 특징으로 하는 질환 이다. 1972년 Hirata 등[1]이 처음 보고한 이래로 일본뿐만 아니라 우리나라에서도 내인성 고인슐린혈증에 의한 저혈당 의 흔한 원인으로 알려져 있으며, 일본에서 특히 서양인에 비해 IAS 환자가 많은 이유는 특정 HLA type 인구가 많은 것으로 DRB1*0406과 관련 있다고 하였다[2]. 인슐린종 역시 드문 질환으로서 90%가 양성 종양이며 매 년 25만 명 당 1명 정도 발생된다. 평균 발병 연령이 50대이 고 60%가 여성이나 다발성 내분비선종(1형)의 경우는 비교 적 젊은 나이에도 발생될 수 있다. 인슐린종의 크기는 직경 1~2 cm 정도가 거의 대부분으로 저혈당 증상을 호소하지 않으면 발견되기 어렵다. 임상적으로 혈당에 대한 반응이 둔 화되어 혈당이 심하게 떨어지지 않으면 증상을 유발하지 않 는다. Octreotide 스캔으로 과반수 환자에서 종양의 위치를 찾을 수 있으며 진단을 위해 동맥조영술을 할 수 있지만 위 음성, 위양성이 많아서 비침습적인 CT, MRI가 추천되며 45~75% 발견 가능하다. IAS는 고인슐린혈증, 공복 저혈당 증상과 함께 자가항체가 확인되면 쉽게 진단할 수 있으며 저혈당 원인이 되는 항체로 는 인슐린자가항체(insulin antibody) 또는 인슐린 수용체 항 체(insulin receptor antibody)가 있다. IAS의 발생에는 그레이 브스병이나 류마티스 관절염과 같은 자가면역 질환이 관련되 어 있다는 보고들[3,4]이 있으며, methimazole, penicillamine, procainamide 등 sulfhydryl기나 amide기를 포함하는 약제 들[4~7]과, captopril[8], imipenem[9], penicillin G[10], 그 리고 α-lipoic acid[11]를 복용한 환자에서 IAS의 발생이 보 고되고 있다. Ichihara 등[5]은 IAS 환자에게 포도당을 정주했을 때 혈 당이 일시적으로 상승하여 내당능장애 상태가 되었다가 이 후 저혈당이 발생됨을 관찰하였고, 이는 포도당 주사에 의해 고인슐린혈증이 유발 되지만 즉시 혈중 항체와 결합하여 유 리 인슐린이 오히려 줄어들어 고혈당이 유발 되고 그 이후 인슐린이 항체에서 유리되면 저혈당이 발생된다고 하였다. 박 등[12]이 보고한 증례도 IAS 환자에서 경구당부하검사를 했을 때 내당능장애를 보였고 이후 고인슐린혈증, 저혈당이 발생되었다. 정 등의 연구[13]에서 인슐린종과 IAS에서 당 화혈색소가 유의한 차이를 보이고 있으며(5.0% vs 5.6%, P < 0.05) IAS 환자에서 대조군의 당화혈색소 5.4% 보다 높 은 것으로 보아 상당수의 IAS 환자에서 내당능장애가 동반 된 것으로 판단된다. 일반적으로 저혈당이 시작되면 생리적으로 즉시 인슐린 분비가 차단된다[14]. 이후 인슐린 길항호르몬들이 순차적으 로 반응을 보이는데 그 중 글루카곤은 가장 빨리 그리고 가 장 중요한 역할을 담당한다[15]. 주로 해당작용 및 당신생을 촉진하게 되며 글루카곤의 반응이 적절하지 못한 경우에는 epinephrine이 다음으로 반응하며 당신생 외에도 인슐린 감 수성 조직에서 포도당의 이용을 제한하게 된다. 저혈당이 지 속되게 되면 성장호르몬과 코르티솔의 작용에 의해 포도당 의 이용이 줄어들고 당신생을 촉진시키게 된다. 내인성 고인슐린혈증에 의한 저혈당증에서의 포도당 길항호르몬 반응

Small Decrements in Systemic Glucose Provoke Increases in Hypothalamic Blood Flow Prior to the Release of Counterregulatory Hormones

OBJECTIVE—The hypothalamus is the central brain region responsible for sensing and integrating responses to changes in circulating glucose. The aim of this study was to determine the time sequence relationship between hypothalamic activation and the initiation of the counterregulatory hormonal response to small decrements in systemic glucose.RESEARCH DESIGN AND METHODS—Nine nondiabetic volunteers underwent two hyperinsulinemic clamp sessions in which pulsed arterial spin labeling was used to measure regional cerebral blood flow (CBF) at euglycemia (∼95 mg/dl) on one occasion and as glucose levels were declining to a nadir of ∼50 mg/dl on another occasion. Plasma glucose and counterregulatory hormones were measured during both study sessions.RESULTS—CBF to the hypothalamus significantly increased when glucose levels decreased to 77.2 ± 2 mg/dl compared with the euglycemic control session when glucose levels were 95.7 ± 3 mg/dl (P = 0.0009). Hypothalamic perfusion was significantly increased before there was a significant elevation in counterregulatory hormones.CONCLUSIONS—Our data suggest that the hypothalamus is exquisitely sensitive to small decrements in systemic glucose levels in healthy, nondiabetic subjects and that hypothalamic blood flow, and presumably neuronal activity, precedes the rise in counterregulatory hormones seen during hypoglycemia.

Lactate overrides central nervous but not β-cell glucose sensing in humans

Lactate has been shown to serve as an alternative energy substrate in the central nervous system and to interact with hypothalamic glucose sensors. On the background of marked similarities between central nervous and β-cell glucose sensing, we examined whether lactate also interacts with pancreatic glucose-sensing mechanisms in vivo. The effects of intravenously infused lactate vs placebo (saline) on central nervous and pancreatic glucose sensing were assessed during euglycemic and hypoglycemic clamp experiments in 10 healthy men. The release of neuroendocrine counterregulatory hormones during hypoglycemia was considered to reflect central nervous glucose sensing, whereas endogenous insulin secretion as assessed by serum C-peptide levels served as an indicator of pancreatic β-cell glucose sensing. Lactate infusion blunted the counterregulatory hormonal responses to hypoglycemia, in particular, the release of epinephrine ( P = .007) and growth hormone ( P = .004), so that higher glucose infusion rates ( P = .012) were required to maintain the target blood glucose levels. In contrast, the decrease in C-peptide concentrations during the hypoglycemic clamp remained completely unaffected by lactate ( P = .60). During euglycemic clamp conditions, lactate infusion did not affect the concentrations of C-peptide and of counterregulatory hormones, with the exception of norepinephrine levels that were lower during lactate than saline infusion ( P = .049) independently of the glycemic condition. Data indicate that glucose sensing of β-cells is specific to glucose, whereas glucose sensing at the central nervous level can be overridden by lactate, reflecting the brain's ability to rely on lactate as an alternative major energy source.

Amplified hormonal counterregulatory responses to hypoglycemia in rats after systemic delivery of a SUR-1-selective K(+) channel opener?

OBJECTIVE— In glucose-sensing neurons, ATP-sensitive K+ channels (KATP channels) are thought to translate metabolic signals into an alteration in neuronal firing rates. Because these neurons express the Kir6.2/SUR-1 isoform of the KATP channel, we sought to examine the therapeutic potential of the SUR-1–selective potassium channel opener (KCO), NN414, to amplify counterregulatory response to hypoglycemia.RESEARCH DESIGN AND METHODS— In vivo dose-response studies with NN414 delivered intravenously to normal Sprague-Dawley rats before the induction of controlled hypoglycemia were performed. Based on these studies, the potential for NN414 to restore counterregulatory responses in chronically cannulated nondiabetic and diabetic BB rats was explored using the in vivo hyperinsulinemic-hypoglycemic clamp technique.RESULTS— NN414 delivered systemically amplified epinephrine responses during acute hypoglycemia and showed a persisting effect to amplify the epinephrine response when given 24 h before the hypoglycemic study. Local delivery of a potassium-channel blocker to the ventromedial hypothalamus reversed the effects of systemic NN414. In addition, NN414 amplified the epinephrine response to hypoglycemia in both nondiabetic and diabetic BB rats with defective hormonal counterregulation.CONCLUSIONS— These studies demonstrate in a variety of rodent models that systemic delivery of Kir6.2/SUR-1–selective KCOs enhance the glucose counterregulatory response to insulin-induced hypoglycemia. Future studies in human subjects are now required to determine their potential as a therapy for hypoglycemia-associated autonomic failure in type 1 diabetes.

Impact of glycemic variations on the regulation of androgen metabolism in obese women with polycystic ovary syndrome

To assess the influence of alterations in glucose concentrations on androgen levels in patients with polycystic ovary syndrome (PCOS) and in healthy controls. Prospective, controlled study. Tertiary care center. Seven patients with PCOS and 20 healthy controls. Hyperinsulinemic glucose clamp study with stepwise reduction of the plasma glucose level from hyperglycemia to hypoglycemia. Concentrations of insulin, C-peptide, cortisol, T, androstenedione, 17-hydroxyprogesterone, DHEA, and DHEAS during hyperglycemia, euglycemia, and hypoglycemia. Total T levels and the free androgen index were significantly higher in the PCOS group at baseline and throughout the clamp. The levels of T, androstenedione, DHEAS, and 17-hydroxyprogesterone were not influenced by short-term changes of plasma glucose concentrations in both groups. However, hypoglycemia led to a significant increase in DHEA levels in PCOS patients as well as in controls. Cortisol levels were not increased during hypoglycemia in either group. In contrast to men, androgen levels are not influenced by short-term changes of plasma glucose levels in PCOS patients and in healthy women. However, DHEA concentrations increase with decreasing glucose levels independently from an activation of the hypothalamic-pituitary-adrenal axis. This supports a gender difference regarding the counterregulatory hormone response to hypoglycemia.

The selective serotonin reuptake inhibitor sertraline enhances counterregulatory responses to hypoglycemia

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for patients with comorbid diabetes and depression. Clinical case studies in diabetic patients, however, suggest that SSRI therapy may exacerbate hypoglycemia. We hypothesized that SSRIs might increase the risk of hypoglycemia by impairing hormonal counterregulatory responses (CRR). We evaluated the effect of the SSRI sertraline on hormonal CRR to single or recurrent hypoglycemia in nondiabetic rats. Since there are time-dependent effects of SSRIs on serotonin neurotransmission that correspond with therapeutic action, we evaluated the effect of 6- or 20-day sertraline treatment on hypoglycemia CRR. We found that 6-day sertraline (SERT) treatment specifically enhanced the epinephrine response to a single bout of hypoglycemia vs. vehicle (VEH)-treated rats (t = 120: VEH, 2,573 +/- 448 vs. SERT, 4,202 +/- 545 pg/ml, P < 0.05). In response to recurrent hypoglycemia, VEH-treated rats exhibited the expected impairment in epinephrine secretion (t = 60: 678 +/- 73 pg/ml) vs. VEH-treated rats experiencing first-time hypoglycemia (t = 60: 2,081 +/- 436 pg/ml, P < 0.01). SERT treatment prevented the impaired epinephrine response in recurrent hypoglycemic rats (t = 60: 1,794 +/- 276 pgl/ml). In 20-day SERT-treated rats, epinephrine, norepinephrine, and glucagon CRR were all significantly elevated above VEH-treated controls in response to hypoglycemia. Similarly to 6-day SERT treatment, 20-day SERT treatment rescued the impaired epinephrine response in recurrent hypoglycemic rats. Our data demonstrate that neither 6- nor 20-day sertraline treatment impaired hormonal CRR to hypoglycemia in nondiabetic rats. Instead, sertraline treatment resulted in an enhancement of hypoglycemia CRR and prevented the impaired adrenomedullary response normally observed in recurrent hypoglycemic rats.

Angiotensin-converting enzyme activity and cognitive impairment during hypoglycaemia in healthy humans

In type 1 diabetes increased risk of severe hypoglycaemia is associated with high angiotensin-converting enzyme (ACE) activity. We tested in healthy humans the hypothesis that this association is explained by the reduced ability of subjects with high ACE activity to maintain normal cognitive function during hypoglycaemia. Sixteen healthy volunteers selected by either particularly high or low serum ACE activity were subjected to hypoglycaemia (plasma glucose 2.7 mmol/L). Cognitive function was assessed by choice reaction tests. Despite a similar hypoglycaemic stimulus in the two groups, only the group with high ACE activity showed significant deterioration in cognitive performance during hypoglycaemia. In the high ACE group mean reaction time (MRT) in the most complex choice reaction task was prolonged and error rate (ER) was increased in contrast to the low ACE group. The total hypoglycaemic symptom response was greater in the high ACE group than in the low ACE group (p=0.031). There were no differences in responses of counterregulatory hormones or in concentrations of substrates between the groups. Healthy humans with high ACE activity are more susceptible to cognitive dysfunction and report higher symptom scores during mild hypoglycaemia than subjects with low ACE activity.

Different Brain Responses to Hypoglycemia Induced by Equipotent Doses of the Long-Acting Insulin Analog Detemir and Human Regular Insulin in Humans

The acylated long-acting insulin analog detemir is more lipophilic than human insulin and likely crosses the blood-to-brain barrier more easily than does human insulin. The aim of these studies was to assess the brain/hypothalamus responses to euglycemia and hypoglycemia in humans during intravenous infusion of equipotent doses of detemir and human insulin. Ten normal, nondiabetic subjects (six men, age 36+/-7 years, and BMI 22.9+/-2.6 kg/m(2)) were studied on four occasions at random during intravenous infusion of either detemir or human insulin in euglycemia (plasma glucose 90 mg/dl) or during stepped hypoglycemia (plasma glucose 90, 78, 66, 54, and 42 mg/dl steps). Plasma counterregulatory hormone response to hypoglycemia did not differ between detemir and human insulin. The glycemic thresholds for adrenergic symptoms were higher with detemir (51 +/- 7.7 mg/dl) versus human insulin (56 +/- 7.8 mg/dl) (P = 0.029). However, maximal responses were greater with detemir versus human insulin for adrenergic (3 +/- 2.5 vs. 2.4 +/- 1.8) and neuroglycopenic (4 +/- 3.9 vs. 2.7+/-2.5) symptoms (score, P < 0.05). Glycemic thresholds for onset of cognitive dysfunction were lower with detemir versus human insulin (51 +/- 8.1 vs. 47 +/- 3.6 mg/dl, P = 0.031), and cognitive function was more deteriorated with detemir versus human insulin (P < 0.05). Compared with human insulin, responses to hypoglycemia with detemir resulted in higher glycemic thresholds for adrenergic symptoms and greater maximal responses for adrenergic and neuroglycopenic symptoms, with an earlier and greater impairment of cognitive function. Additional studies are needed to establish the effects of detemir on responses to hypoglycemia in subjects with diabetes.

Key Role for AMP-Activated Protein Kinase in the Ventromedial Hypothalamus in Regulating Counterregulatory Hormone Responses to Acute Hypoglycemia

To examine in vivo in a rodent model the potential role of AMP-activated protein kinase (AMPK) within the ventromedial hypothalamus (VMH) in glucose sensing during hypoglycemia. Using gene silencing technology to selectively downregulate AMPK in the VMH, a key hypothalamic glucose-sensing region, we demonstrate a key role for AMPK in the detection of hypoglycemia. In vivo hyperinsulinemic-hypoglycemic (50 mg dl(-1)) clamp studies were performed in awake, chronically catheterized Sprague-Dawley rats that had been microinjected bilaterally to the VMH with an adeno-associated viral (AAV) vector expressing a short hairpin RNA for AMPKalpha. In comparison with control studies, VMH AMPK downregulation resulted in suppressed glucagon ( approximately 60%) and epinephrine (approximately 40%) responses to acute hypoglycemia. Rats with VMH AMPK downregulation also required more exogenous glucose to maintain the hypoglycemia plateau and showed significant reductions in endogenous glucose production and whole-body glucose uptake. We conclude that AMPK in the VMH plays a key role in the detection of acute hypoglycemia and initiation of the glucose counterregulatory response.