The Neurological and Developmental Effects of Neonatal Hypoglycemia: A Follow-up of 22 Cases

Twenty-two infants in whom hypoglycemia (blood sugar less than 20 mg./100 ml.) was noted during the first few days of life were followed up when eight to 30 months of age. In eight such symptoms as muscular tremors, cyanosis, apneic spells and convulsions were associated with the hypoglycemia; five of these had abnormal central nervous system signs and retarded development. One other had possible impairment of development and another had a recurrence of hypoglycemia after having been well for four years. Fourteen of the 22 infants had no symptoms associated with the hypoglycemia, and on follow-up only two of these showed possible impairment. The rest were normal.This preliminary study suggests that hypoglycemia associated with neurological symptoms in the newborn period carries a poor prognosis with respect to permanent neurological damage. Asymptomatic hypoglycemia may have a relatively good prognosis.     

Clinical, biological and genetic analysis of 8 cases of congenital isolated adrenocorticotrophic hormone (ACTH) deficiency

Background

Congenital isolated adrenocorticotrophic hormone (ACTH) deficiency may be rare, but it could be an underestimated cause of neonatal death. Our objective was to shorten the time between first symptoms and diagnosis.

Methods

This single-centre retrospective case-cohort study was carried out on eight consecutive patients.

Results

Two had the neonatal form and 6 the late onset form. Six were admitted to an intensive care unit at least once for seizures with hypoglycemia, major hypothermia, fever, and/or collapsus. The 2 neonatal cases presented with hypoglycemia and in a state of “apparent death” at birth or hypothermia (29°C) at 6 days. All 6 late onset cases had also been admitted to an emergency department 1–3 times, but had left hospital incorrectly diagnosed. Their first symptoms were noted at 3–12.3 years, and they were diagnosed at 3.3–14.4 years. All had hypoglycemia, and 4 had had seizures. The presenting symptoms were vomiting and/or abdominal pain, asthenia, irritability, difficulty with physical activities, and anorexia. The school performance of 4 deteriorated. Two underwent psychotherapy and treatment for depression, which was stopped when Hydrocortisone® replacement therapy began.The plasma concentrations in spontaneous hypoglycemia were: ACTH<5 to 17.1 pg/mL, with concomitant cortisol <3.5 to 37 ng/mL. The plasma dehydroepiandrosterone sulfate (DHAS) concentrations were low in the 7 evaluated. The coding sequence of TPIT was normal in all.

Conclusion

Several unexplained symptoms in a child, mainly gastro-intestinal symptoms and seizures due to hypoglycemia, may indicate ACTH deficiency. A low or normal basal plasma ACTH despite concomitant low cortisol at 8 a.m. and/or in spontaneous hypoglycemia, associated with low DHAS, in a patient not given corticosteroids is highly suggestive of ACTH deficiency. The isolated character of ACTH deficiency must be confirmed by determining the other hypothalamic-pituitary functions, and Hydrocortisone® replacement therapy initiated in emergency.     

Value of antenatal diagnosis of abnormalities of the urinary tract.

OBJECTIVE--To assess the value of antenatal diagnosis of abnormalities of the urinary tract on ultrasonography. DESIGN--Retrospective study. SETTING--Two obstetric units in Glasgow. SUBJECTS--62 Fetuses in which renal abnormalities were diagnosed on antenatal ultrasonography. INTERVENTIONS--Six fetuses had their bladders aspirated to determine renal function. Fifteen pregnancies were terminated on the basis of the findings on antenatal ultrasonography, and if possible necropsy was performed on the fetuses. In babies who were born alive the final diagnosis was made by postnatal ultrasonography, intravenous urography, radionuclide scanning, cystography, and, in those who died in the early neonatal period, necropsy. Neonates who were referred with a known obstructed kidney had nephrostomy or pyeloplasty. END POINT--Assessment of the value of antenatal diagnosis of renal abnormalities on ultrasonography for babies who had no clinical evidence of disease postnatally. MAIN RESULTS--Eighteen fetuses did not survive birth; the antenatal diagnosis was accurate in all 18. Of the 44 babies born alive, five had normal urinary tracts, in two of whom antenatal ultrasonography had probably indicated a false positive diagnosis. Fourteen babies died during the early neonatal period. Twenty five babies with renal abnormalities were followed up; the antenatal diagnosis was inaccurate for 10 of them, the commonest misdiagnosis being hydronephrosis for multicystic kidney and vice versa, and there was one false positive diagnosis. The initial clinical findings in 14 babies would have led to the early detection of a urological abnormality. In the 30 babies with no clinical evidence of disease the antenatal diagnosis was of definite value in eight, probable value in 15, and marginal value in seven. Overall, an accurate antenatal diagnosis was made in 46 of the 62 cases (74%); in 12 cases renal disease was detected but its specific nature was not determined; and in four cases the diagnosis was misleading. CONCLUSIONS--The overall value of antenatal diagnosis is that it indicates early termination of fetuses with fatal renal disease, prepares parents and medical staff for the likelihood of serious neonatal problems, and shows abnormalities of the urinary tract that may not be detected postnatally.     

Clinical Presentation and Diagnostic Approach to Hypoglycemia in Adults Without Diabetes Mellitus

ObjectiveTo review the clinical presentation, causes, and diagnostic approach to spontaneous hypoglycemia in adults without diabetes mellitus.MethodsA literature review was performed using the PubMed and Google Scholar databases.ResultsHypoglycemia is uncommon in people who are not on glucose-lowering medications. Under normal physiologic conditions, multiple neural and hormonal counterregulatory mechanisms prevent the development of abnormally low levels of plasma glucose. If spontaneous hypoglycemia is suspected, the Whipple triad should be used to confirm hypoglycemia before pursuing further diagnostic workup. The Whipple criteria include the following: (1) low levels of plasma glucose, (2) signs or symptoms that would be expected with low levels of plasma glucose, and (3) improvement in those signs or symptoms when the level of plasma glucose increases. Spontaneous hypoglycemia can be caused by conditions that cause endogenous hyperinsulinism, including insulinoma, postbariatric hypoglycemia, and noninsulinoma pancreatogenous hypoglycemia. Spontaneous hypoglycemia can also be seen with critical illness, hepatic or renal dysfunction, hormonal deficiency, non–diabetes-related medications, and non–islet cell tumors. The initial diagnostic approach should begin by obtaining a detailed history of the nature and timing of the patient’s symptoms, medications, underlying comorbid conditions, and any acute illness. A laboratory evaluation should be conducted at the time of the spontaneous symptomatic episode. Supervised tests such as a 72-hour fast or mixed-meal test may be needed to recreate the situation under which the patient is likely to experience symptoms.ConclusionWe provide an overview of the physiology of counterregulatory response to hypoglycemia, its causes, and diagnostic approaches to spontaneous hypoglycemia in adults.     

Sequelae of an 125I-Fibrinogen Detected Thrombus

Forty-four patients who had a deep vein thrombosis detected with the fibrinogen uptake test were followed up three to four years later. The mild aching pains and ankle swelling that were present at the time of the thrombosis persisted or got worse in many, but there was no increase in the incidence of varicose veins. The minor self-limiting thrombosis detected with the fibrinogen uptake test should not be considered innocuous, for it can cause long-lasting symptoms.     

新生儿Ⅰ期胃代食管术治疗Ⅲa型食管闭锁的疗效观察

目的:探讨Ⅰ期胃代食管术治疗Ⅲa型食管闭锁的疗效。方法:对2008年3月至2013年6月我院采用Ⅰ期胃代食管术治疗的8例Ⅲa型食管闭锁进行回顾性分析。其中男6例,女2例,食管两盲端距离均大于3 cm。结果:所有患儿均顺利完成手术。6例治愈出院,1例死亡,1例家长放弃治疗。术后5例有严重肺炎,近期吻合口瘘2例。随访6个月至5年,吻合口狭窄2例,均行食管扩张术治愈,轻度胃食管反流4例,均未行抗反流手术,采用少量多餐及体味喂养治疗后症状缓解。结论:新生儿期采用Ⅰ期胃代食管术治疗Ⅲa型食管闭锁临床可行,避免了分期手术,缩短了治疗周期,有助于提高治愈率。     

Pancreatic Disease in Infancy and Childhood—Surgical Implications

Surgeons whose practice involves many infants and children should be acquainted with all abnormalities of pancreatic malformation and function. Conditions amenable to surgical treatment are few, but serious.Trauma to the pancreas in childhood is most commonly diagnosed by fever, leukocytosis, rectus spasm and elevated serum amylase. Drainage of the lesser sac and debridement of devitalized tissue may prevent the sequelae of pseudocyst formation which seems to follow the untreated injury. True congenital cysts are characterized by an epithelial lining.Mucoviscidosis complicated by meconium ileus remains a challenging disease of the newborn that requires early operation. Ten per cent of infants with cystic fibrosis may be threatened by intestinal obstruction from this cause. Some children surviving the newborn period go on to develop obstruction later.Annular malformation of pancreas may produce upper intestinal (duodenal) obstructive symptoms immediately after birth. Surgical correction by duodenojejunostomy should be postponed only long enough to correct severe fluid or electrolyte imbalances.Idiopathic spontaneous hypoglycemia has the most serious prognosis if convulsions are allowed to recur. Increased metabolic rates in infants increase the need for control of blood sugar levels by either administration of cortisone or pancreatic resection. If adenoma is the cause, a conservative resection of the tumor suffices. If serial frozen section fails to reveal either tumor or hypertophy of insulin-producing cells, blind pancreatectomy may be indicated, for irreversible brain damage develops early in uncontrolled hypoglycemia.     

Predictors for Mild and Severe Hypoglycemia in Insulin-Treated Japanese Diabetic Patients

The objective of this study was to explore predictors, including social factors, lifestyle factors, and factors relevant to glycemic control and treatment, for mild and severe hypoglycemia in insulin-treated Japanese diabetic patients. This study included 123 insulin-treated diabetic patients who were referred to the diabetes clinic between January and July 2013 at Shiga University of Medical Science Hospital. After a survey examining the various factors, patients were followed for 6 months. During the follow-up period, blood glucose was self-monitored. Mild hypoglycemia was defined as blood glucose level 50–69 mg/dl, and severe hypoglycemia was defined as blood glucose level ≤49 mg/dl. Multinomial logistic regression was used to estimate the adjusted odds ratio (OR) and 95% confidence interval (CI) of each factor for mild and severe hypoglycemia. During the 6-month follow-up period, 41 (33.3%) patients experienced mild hypoglycemia, and 20 (16.3%) experienced severe hypoglycemia. In multivariable-adjusted analyses, assistance from family members at the time of the insulin injection [presence/absence, OR (95% CI): 0.39 (0.16–0.97)] and drinking [current drinker/non- and ex-drinker, OR (95% CI): 4.89 (1.68–14.25)] affected mild hypoglycemia. Assistance from family members at the time of insulin injection [presence/absence, OR (95% CI): 0.19 (0.05–0.75)] and intensive insulin therapy [yes/no, OR (95% CI): 3.61 (1.06–12.26)] affected severe hypoglycemia. In conclusion, our findings suggest that not only a factor relevant to glycemic control and treatment (intensive insulin therapy) but also a social factor (assistance from family members) and a lifestyle factor (current drinking) were predictors for mild or severe hypoglycemia in Japanese insulin-treated diabetic patients.     

Hypoglycemia-dependent beta2-adrenoceptor downregulation: a contributing factor to hypoglycemia unawareness in patients with Type-1 diabetes?

To evaluate the influence of the incidence and unawareness of hypoglycemia on lymphocyte beta2-adrenoceptor densities, we measured beta2-adrenoceptor density using [125I]-iodocyanopindolol and CGP 12177 before and after 1 week of treatment optimization in 33 adults with type-1 diabetes mellitus. Diabetes treatment of all patients was modified to improve their glycemic control. During this week, all patients had to complete a protocol with 7 daily glucose measurements, one of which was at night. The subjective symptoms were evaluated in case of hypoglycemia. A significant correlation between a hypoglycemia incidence below (but not above) the threshold of 2.75 mmol/l (50 mg/dl) and beta2-adrenoceptor densities on lymphocytes was found after the study week (r = -0.72, p < 0.00001). Nine patients suffering from hypoglycemia unawareness had a significantly higher incidence of hypoglycemia (p < 0.002) and lower beta2-adrenoceptor densities on lymphocytes compared to 24 patients who recognized all of their hypoglycemic episodes (p < 0.004). We conclude that downregulation of beta2-adrenoceptor densities on lymphocytes occurs as a result of recurrent hypoglycemia defined as glucose levels of < 2.75 mmol/l. Beta2-adrenoceptor densities are decreased in patients with subjective hypoglycemia unawareness and might contribute to the reduced beta-adrenergic sensitivity in this subgroup of patients.     

Influence of Severe Hypoglycemia on Mitochondrial and Plasma Membrane Function in Rat Brain

Abstract: Previous experiments have shown that severe hypoglycemia disrupts cerebral energy state in spite of a maintained cerebral oxygen consumption, suggesting uncoupling of oxidative phosphorylation. Other studies have demonstrated that hypoglycemia leads to loss of cerebral cortical phospholipids and phospholipid-bound fatty acids. The objective of the present study was, therefore, to study respiratory characteristics of brain mitochondria during severe hypoglycemia and to correlate respiratory activity to mitochondrial phospholipid composition. Mitochondria were isolated after 30 or 60 min of hypoglycemia with ceased EEG activity, and after a 90-min recovery period, and their resting (state 4) and ADP-stimulated (state 3) oxygen consumption rates and phospholipids and phospholipid-bound fatty acid content were measured. After 30 min of hypoglycemia, state 3 respiration decreased without any increase in state 4 respiration or change in ADP/O ratio. This decrease, which occurred with glutamate plus malate—but not with succinate—as substrates, was partly reversed by addition of bovine serum albumin and KCI. Chemical analyses of isolated mitochondria did not reveal changes in their phospholipid or fatty acid content. The results thus failed to account for the dissociation of cerebral energy state and oxygen consumption. It is emphasized, though, that uncoupling may well occur in vivo due to accumulation of free fatty acids and “futile cycling” of K⁺ and Ca²⁺. After 60 min of hypoglycemia, a moderate decrease in state 3 respiration was observed also with succinate as substrate, and there was some decrease in ADP/O ratios in KCI-containing media. However, the changes in ADP/O ratios were more conspicuous during recovery; in addition, state 4 respiration increased significantly. It is concluded that changes in mitochondrial function after 30 min of hypoglycemia are potentially reversible but that true mitochondrial failure develops in the recovery period following 60 min of hypoglycemia. This conclusion was corroborated by results demonstrating incomplete recovery of cerebral energy state. Since EEG and sensory evoked potentials return after 30 min but not after 60 min of hypoglycemia it seemed difficult to explain failure of return of electrophysiological function after 60 min of hypoglycemia solely by mitochondrial dysfunction; plasma membrane function was therefore assessed by measurements of extracellular potassium activity ([K⁺]_e). The results showed that whereas [K⁺]_e remained close to control in the recovery period following 30 min of hypoglycemia it rose progressively during recovery following 60 min of hypoglycemia. Possibly, inhibition of Na⁺ K⁺–activated ATPase could contribute to the permanent loss of spontaneous or evoked electrical activity.     

Is there a link between cot death and child abuse?

Forty five babies delivered in Oxford obstetric units who subsequently died unexpectedly in infancy were compared with 134 controls matched for maternal age, social class, parity, and year of birth to see whether five factors identified in an earlier study as predictive of subsequent child abuse would also predict the sudden infant death syndrome. Epidemiological findings had suggested certain similarities between the two events. In contrast with babies who were abused, four of the five factors did not distinguish between babies who died suddenly and unexpectedly and their controls, but there was a slight increase in the proportion of mothers of babies who died suddenly and unexpectedly for whom nursing staff thought that support and advice on feeding the baby were needed. Factors predictive of child abuse did not predict sudden infant death in this study.     

Protective effect of breast feeding against infection.

OBJECTIVE--To assess the relations between breast feeding and infant illness in the first two years of life with particular reference to gastrointestinal disease. DESIGN--Prospective observational study of mothers and babies followed up for 24 months after birth. SETTING--Community setting in Dundee. PATIENTS--750 pairs of mothers and infants, 76 of whom were excluded because the babies were preterm (less than 38 weeks), low birth weight (less than 2500 g), or treated in special care for more than 48 hours. Of the remaining cohort of 674, 618 were followed up for two years. INTERVENTIONS--Detailed observations of infant feeding and illness were made at two weeks, and one, two, three, four, five, six, nine, 12, 15, 18, 21, and 24 months by health visitors. MAIN OUTCOME MEASURE--The prevalence of gastrointestinal disease in infants during follow up. RESULTS--After confounding variables were corrected for babies who were breast fed for 13 weeks or more (227) had significantly less gastrointestinal illness than those who were bottle fed from birth (267) at ages 0-13 weeks (p less than 0.01; 95% confidence interval for reduction in incidence 6.6% to 16.8%), 14-26 weeks (p less than 0.01), 27-39 weeks (p less than 0.05), and 40-52 weeks (p less than 0.05). This reduction in illness was found whether or not supplements were introduced before 13 weeks, was maintained beyond the period of breast feeding itself, and was accompanied by a reduction in the rate of hospital admission. By contrast, babies who were breast fed for less than 13 weeks (180) had rates of gastrointestinal illness similar to those observed in bottle fed babies. Smaller reductions in the rates of respiratory illness were observed at ages 0-13 and 40-52 weeks (p less than 0.05) in babies who were breast fed for more than 13 weeks. There was no consistent protective effect of breast feeding against ear, eye, mouth, or skin infections, infantile colic, eczema, or nappy rash. CONCLUSION--Breast feeding during the first 13 weeks of life confers protection against gastrointestinal illness that persists beyond the period of breast feeding itself.     

Leucine-induced hypoglycemia in a family: effect of diphenylhydantoin, oxprenolol, and diazoxide

The present report describes a mother and 2 children with leucine-induced hypoglycemia (LIH). Hypoglycemic episodes following high-protein meals first appeared at age 4-7 months. Leucine-stimulation tests triggered marked hyperinsulinism and hypoglycemia in the children and a milder but abnormal response in the mother. To evaluate the therapeutic effects and to study the mechanism of hyperinsulinism in LIH, the leucine test was repeated under treatment with diphenylhydantoin, oxprenolol (a beta-blocker), and diazoxide. Diazoxide abolished hyperinsulinism; diphenylhydantoin did not affect the response to leucine; and oxprenolol, tested in the mother only, increased hyperinsulinism and hypoglycemia. Our results indicate that LIH is an autosomal dominant disorder; LIH may persist into adulthood with milder clinical symptoms and chemical response to leucine; diazoxide is the treatment of choice in LIH. Considering the effects of the three agents on stimulated release of insulin, it is concluded that leucine triggers hyperinsulinism by a mechanism different from that of glucose and beta-adrenergic receptors.     

Treating heartburn in pregnancy: comparison of acid and alkali mixtures.

A randomised crossover trial was performed in 55 pregnant women who complained of heartburn to see whether alkali or acid treatment alleviated it. Each woman was given a week''s treatment with an acid mixture, an alkali mixture, and a placebo in randomised order. Both acid and alkali mixtures were better than placebo, but there was no significant difference between the acid and alkali treatments. Together with the inconsistent reports of some patients, these findings suggest that both acid reflux and bile regurgitation may cause heartburn in pregnant women and that other factors may also play a part. Because the cause of heartburn may be difficult to determine, treatment should be empirical. If the patient does not respond to seven days'' acid treatment an alkali mixture should be prescribed; there is a 98% chance that one of these treatments will relieve symptoms.     

Comparison of Birth Weight/Gestation Distribution in Cases of Stillbirth and Neonatal Death According to Lesions Found at Necropsy

The birth weight/gestation distribution of a large series of cases of perinatal death has been analysed according to the lesion (or lesions) present at necropsy. Among the lesions associated with low gestation babies dying with hyaline membranes have a much higher mean birth weight for gestation than either the babies with intraventricular haemorrhage or “no cause found.” Among infants dying of intrapartum asphyxia or cerebral birth trauma it was found that those who were stillborn with trauma had, at term, a significantly higher mean birth weight than the control livebirths, and that, at all gestations, the stillbirths with trauma were, on average, heavier than the babies dying neonatally with this lesion. Cases of intrapartum asphyxia were smaller than the stillbirths with trauma, but those dying during the second stage of labour were larger than those dying during the first stage.Cases of intrauterine pneumonia—that is, stillbirths and first-day deaths—were also shown to be larger for length of gestation than cases of extrauterine pneumonia—that is, deaths between the second and the 28th day. The cases with haemorrhagic pneumonia, however, were, at least at term, smaller than the cases of extrauterine pneumonia, and cases of massive pulmonary haemorrhage showed evidence of growth retardation at all gestations.     

Hormonal responses to hypoglycemia in orthostatic hypotension patients with adrenergic insufficiency

Glucagon, growth hormone and cortisol responses to insulin-induced hypoglycemia have been studied in nine normal subjects and four patients with orthostatic hypotension who also had markedly deficient sympathoadrenal medullary responses. Absence of catecholamine responses to hypoglycemia does not prevent the other hormonal responses. Glucagon, growth hormone and cortisol secretion appear to be evoked independently from the catecholamine response during hypoglycemia. Elevated basal cortisol levels are the probable cause of a delay in the nadir of hypoglycemia observed in patients with adrenergic insufficiency. The sympathetic nervous system dysfunction in patients with neurogenic orthostatic hypotension may include deficient adrenal medullary responses although other counterregulatory responses remain functional.     

Outcome of pregnancy in underweight women after spontaneous and induced ovulation

Low maternal weight before pregnancy and poor weight gain during pregnancy are known to result in an increased prevalence of low birthweight infants. Low body weight is also an important cause of amenorrhoea. The hypothesis that amenorrhoeic underweight women who become pregnant after induction of ovulation are more at risk of delivering low birthweight infants than underweight women who ovulate spontaneously was investigated. Forty one pregnant women in whom ovulation had been induced and 1212 in whom ovulation was spontaneous were studied. Women ovulating spontaneously whose weight was normal and who showed good weight gain during pregnancy (>450 g a week) had the lowest incidence (6%) of babies who were small for gestational age. Underweight women (body mass index <19·1) who ovulated spontaneously had a threefold increased risk of delivering babies who were small for gestational age (18%). Overall, the women in whom ovulation had been induced had an even higher risk of babies who were small for dates (25%), and this risk was greatest (54%) in those who were underweight.The outcome of pregnancy is related to weight before conception, which in many cases reflects nutritional state; lack of spontaneous ovulation indicates an increased risk of producing a small for dates infant. The most suitable treatment for infertility secondary to weight related amenorrhoea is therefore dietary rather than induction of ovulation.     

Prevalence of urinary incontinence.

The prevalence of urinary incontinence was investigated by determining the number of incontinent patients under the care of various health and social service agencies in two London boroughs and by a postal survey of the 22 430 people aged 5 years and over on the practice lists of 12 general practitioners in different parts of the country. The prevalence of incontinence known to the health and social service agencies was 0.2% in women and 0.1% in men aged 15-64 and 2.5% in women and 1.3% in men aged 65 and over. The postal survey, to which 89% of the people whose correct address was known replied, showed a prevalence of urinary incontinence of 8.5% in women and 1.6% in men aged 15-64 and 11.6% in women and 6.9% in men aged 65 and over. Nulliparous women had a lower prevalence than those who had had one, two, or three babies, but within the parity range of one to three there were no differences in prevalence. The prevalence was appreciably increased in women who had had four or more babies. Incontinence was moderate or severe in a fifth of those who reported it in the postal survey, of whom less than a third were receiving health or social services for the condition. Incontinence is a common symptom, and many unrecognised cases appear to exist. There may be considerable scope for improving its management.     

Hypoglycemias.

Low plasma glucose concentrations that may or may not be sufficiently low to result in symptoms can be observed as a concomitant of several diverse diseases. Treatment of the primary underlying disorder usually alleviates the hypoglycemia. For patients whose primary symptom is that of hypoglycemia, it is essential to confirm that the plasma glucose concentration is low during the occurrence of symptoms. Symptoms that occur after meals usually are mild and rarely signify serious disease. With rare exceptions, hypoglycemia resulting in major symptoms occurs in the food-deprived state. Lower concentrations of plasma insulin and C-peptide and a concomitant low plasma glucose are major clues to a correct diagnosis.     

Hyperglycemia does not increase basal hypothalamo-pituitary-adrenal activity in diabetes but it does impair the HPA response to insulin-induced hypoglycemia

Recently, we established that hypothalamo-pituitary-adrenal (HPA) and counterregulatory responses to insulin-induced hypoglycemia were impaired in uncontrolled streptozotocin (STZ)-diabetic (65 mg/kg) rats and insulin treatment restored most of these responses. In the current study, we used phloridzin to determine whether the restoration of blood glucose alone was sufficient to normalize HPA function in diabetes. Normal, diabetic, insulin-treated, and phloridzin-treated diabetic rats were either killed after 8 days or subjected to a hypoglycemic (40 mg/dl) glucose clamp. Basal: Elevated basal ACTH and corticosterone in STZ rats were normalized with insulin but not phloridzin. Increases in hypothalamic corticotrophin-releasing hormone (CRH) and inhibitory hippocampal mineralocorticoid receptor (MR) mRNA with STZ diabetes were not restored with either insulin or phloridzin treatments. Hypoglycemia: In response to hypoglycemia, rises in plasma ACTH and corticosterone were significantly lower in diabetic rats compared with controls. Insulin and phloridzin restored both ACTH and corticosterone responses in diabetic animals. Hypothalamic CRH mRNA and pituitary pro-opiomelanocortin mRNA expression increased following 2 h of hypoglycemia in normal, insulin-treated, and phloridzin-treated diabetic rats but not in untreated diabetic rats. Arginine vasopressin mRNA was unaltered by hypoglycemia in all groups. Interestingly, hypoglycemia decreased hippocampal MR mRNA in control, insulin-, and phloridzin-treated diabetic rats but not uncontrolled diabetic rats, whereas glucocorticoid receptor mRNA was not altered by hypoglycemia. In conclusion, despite elevated basal HPA activity, HPA responses to hypoglycemia were markedly reduced in uncontrolled diabetes. We speculate that defects in the CRH response may be related to a defective MR response. It is intriguing that phloridzin did not restore basal HPA activity but it restored the HPA response to hypoglycemia, suggesting that defects in basal HPA function in diabetes are due to insulin deficiency, but impaired responsiveness to hypoglycemia appears to stem from chronic hyperglycemia.