A new aid to insulin coma therapy

Summary A new method of controlling insulin coma has been developed. It lessens some of the difficulties which have complicated deep insulin coma therapy.     

Electric stimulation and insulin coma

Summary Observations with nonconvulsive stimulation during insulin coma have been presented. The method is useful in arousing patients from coma, provided that they have not entered a deep phase. Adrenalin and blood sugar responses suggest that activation of the diencephalic pituitary-adrenal axis occurs. The theory that during insulin coma a successive inactivation of phylogenetic layers within the brain takes place is supported by the observations reported here. Therapeutic results suggest a favorable comparison with deep insulin coma, provided a differential and dynamic approach is followed. Complications, such as delayed and protracted coma, have not been encountered. Treatment time is shortened to about two hours, and the average number of treatments is about 40.Read at the 109th annual meeting of the American Psychiatric Association at Los Angeles, May 1953.     

Observations on organic brain damage and clinical improvement following protracted insulin coma

Summary A study of eight cases of chronic schizophrenics who developed protracted coma during insulin shock therapy is reported. Five of the eight patients showed a marked improvement after protracted coma, and three remained unimproved. The improvement consisted of loss of tension and hostility. Patients became friendly, affable, relaxed and interested in the environment. In spite of the return of delusional systems, the improved patients were able to function on a higher level than previously. In four of the five improved patients, improvement was preceded by severe organic brain deficit of varied duration. The organic deficit was demonstration through clinical observation, a battery of psychological tests and electro-encephalograms. Improvement is attributed to the organic brain damage which results in disruption of associative pathways not unlike the disruption in lobotomy.Published with permission of the chief medical director, Department of Medicine and Surgery, Veterans Administration, who assumes no responsibility for the opinions expressed or conclusions drawn by the author.     

The use of glucagon in insulin coma therapy

Summary The use of glucagon in the termination of insulin coma therapy has been discussed. The advantages over previous techniques of termination were described. Clinical experience with 41 patients who had a total of 739 comas showed no untoward reactions with the use of glucagon. No permanent residual effects were noted, and only transitory reactions, such as delayed coma, muscular twitching and secondary comas were reported in six instances.It has been demonstrated that glucagon is an effective, reliable and safe drug in the termination of insulin coma therapy. Its introduction as a therapeutic agent has demonstrated once more the many benefits which can be derived from basic medical research.From the department of neurology and psychiatry, Chicago Wesley Memorial Hospital and from the department of neurology and psychiatry, Northwestern University Medical School, Chicago, Ill.     

SECRETION OF HUMAN GROWTH HORMONE DURING INSULIN COMA AND ELECTROSHOCK THERAPIES

The responses of plasma HGH during psychiatric shock therapies were investigated, and the mechanisms of HGH secretion and of shock therapies were discussed. 1. The response following a sinall dose of i.v. insulin administrotion. a) The plasma HGH following 0.1 U/kg of i.v. insulin in schizophrenic patients showed marked elevation in six out of seven cases. It reached to the peak value of 30.4±9.2 mμg/ml between 60 and 90 minutes after i.v. insulin. b) This type of response was not affected by the various psychotropic drugs that were administered orally in controlling the mental symptoms of the patients. c) Intramuscular injection of chlorpromazine (30–50 mg) did not alter the pattern of the plasma HGH response. 2. Insulin coma therapy a) A marked elevation of plasma HGH level was observed in all cases of schizophrenia during insulin coma therapy. The peak value was 9–32 mμg/ml (average 22.6±8.1 mμg/ml). b) A tendency of delay in reaching the peak value was observed in the determination performed in the second week of coma days as compared to the initial determination in the early days of insulin coma. A tendency was observed that better therapeutic results were correlated with the absence of or decrease in the delay in reaching the peak value in the course of insulin coma therapy. c) The protracted insulin coma was associated with the marked decrease in the magnitude of the peak value of plasma HGH as compared to the initial determination, suggesting the presence of a fatigued state of the central mechanism regulating the secretion of HGH. 3. Electroshock therapy a) Elevation of the plasma HGH level was observed after electroshock therapy in five of six cases of schizophrenia. A non-responsive case was found to be moderately obese. A case of depression and a case of atypical psychosis lacked HGH response after EST in the absence of obesity. b) The peak value after the electroshock therapy was lower than the one during insulin coma therapy or after administration of a small dose of i.v. insulin. The average peak value after EST was 8.1±6.8 mμg/ml. c) The responsivity of plasma HGH was found to be unrelated to the various prernedications, such as i.v. thiopental and succinylcholine chloride. It was also concluded that the presence or absence of generalized convulsion was not related to the responses of HGH following EST. d) No correlation was found between the changes of blood sugar level and the type of plasma HGH responses following the EST. It was suggested that the elevation of HGH at the time of electroshock therapy was induced by the direct electric stimulation of the hypothalamic center, but the effect of stimulating the HGH secretion was much lower than that induced by the insulin coma or i.v. insulin administration.     

Insulin coma therapy: Decrease of plasma tryptophan in man

Summary A biochemical study was performed in two patients submitted to insulin coma therapy. The injection of insulin resulted in a decrease of free and total tryptophan as well as tyrosine in plasma, while NEFA were not influenced by this treatment. The ratio of tryptophan to tyrosine was enhanced. The administration of glucose after insulin provoked an increase of free and total tryptophan. The results support the hypothesis that in man insulin may favor the uptake of tryptophan by the brain, and enhance the synthesis of cerebral serotonin.     

Lessons from the insulin story in psychiatry

For nearly 20 years, from the mid-1930s until the mid-1950s, early cases of schizophrenia were treated, and surprisingly successfully treated, by deep insulin coma therapy. This paper is an attempt to explore what, if any, lessons there are to be gained for us 30 years later from a treatment regime that turned out to have nothing to do with insulin per se. Such lessons as there may be from our recent historical past may help us to foster our critical acumen and commonsense as we try in our daily practice to understand how we can best help our patients in safety.     

Modulation of dopamine receptor supersensitivity by chronic insulin: implication in schizophrenia

Haloperidol-induced increases in the number of dopamine receptors, as measured by [³H]spiperone binding to striatal membranes, do not occur in rats repeatedly treated with insulin in doses eliciting pronounced hypoglycemia. Given alone, however, insulin has no effect on [³H]spiperone binding in normal rats. These findings demonstrate a modulating effect of insulin on brain dopamine receptor sensitization. This effect might be relevant to the mechanism of insulin coma therapy in schizophrenia and is consistent with and supports the dopaminergic hypothesis of this disorder.     

Characterization of insulin secretion in Valproate-treated patients with epilepsy

PURPOSE: Valproate (VPA) treatment has been reported to be associated with obesity and high fasting serum insulin concentrations in parallel with an unfavorable serum lipid profile and hyperandrogenism and polycystic ovaries in women. The pathogenetic mechanism underlying these changes has remained unknown, although several mechanisms have been implicated. METHODS: Fifty-one patients receiving monotherapy (31 male and 20 female patients) were included in this study, with 45 (23 male and 22 female) healthy control subjects. These participants were interviewed, clinically examined, and blood samples for fasting plasma glucose, serum insulin, proinsulin, and C-peptide concentrations were taken after an overnight fast. RESULTS: The valproate-treated patients had fasting hyperinsulinemia (11.30 +/- 6.23 pM vs. 6.28 +/- 4.66 pM in the control subjects; p < 0.001), although the fasting serum proinsulin and C-peptide concentrations were not significantly higher in the patients than in the control subjects. In addition, proinsulin/insulin (0.30 +/- 0.14) and C-peptide/insulin ratios (35.48 +/- 24.09) were lower (p < 0.001) in the VPA-treated patients when compared with the control subjects (0.53 +/- 0.36 and 94.27 +/- 61.85, respectively), and they also had lower fasting plasma glucose concentrations (4.72 +/- 0.35 mM) than the control subjects (5.12 +/- 0.58 mM; p < 0.01). CONCLUSIONS: This study suggests that valproate does not induce insulin secretion but might interfere with the insulin metabolism in the liver, resulting in higher insulin concentrations in the peripheral circulation. These changes are seen irrespective of concomitant weight gain, suggesting that increased insulin concentrations induce weight gain and not vice versa.     

Brain metabolism after recurrent insulin induced hypoglycaemic episodes: a PET study.

Neuropsychological testing was carried out and the rate of oxygen metabolism in the brain was measured by PET in 15 highly selected patients with type 1 diabetes. The aim was to investigate the impact on the brain of hypoglycaemic comas resulting from insulin treatment. No significant difference was found between nine patients with a history of more than 10 hypoglycaemic comas and six others who denied any history of such events. These data suggest that intensified insulin treatment, although increasing the frequency of hypoglycaemic coma, may not always be harmful for the brain. This may be explained by the limited duration of hypoglycaemic coma induced by conventional insulin treatment.     

胰岛素强化治疗重型颅脑损伤合并糖尿病

目的探讨胰岛素强化治疗对重型颅脑损伤(STBI)合并糖尿病患者的临床疗效及预后的影响。方法选择入住重症监护病房(ICU)既往有糖尿病史的重型颅脑损伤患者80例,随机分为治疗组和对照组,每组40例,治疗组给予7 d胰岛素强化治疗,随后给予常规血糖控制,对照组全程常规血糖控制。强化胰岛素治疗组血糖控制目标为4.4~8.3 mmol/L,常规血糖控制目标为4.4~11.1 mmol/L。结果伤后随访6月按(GOS)评分评价疗效,治疗组恢复良好率较对照组组提高15%,死亡率下降17%(P0.05),ICU住院时间、机械通气时间、院内感染发生率均低于对照组(P0.05)。结论短期胰岛素强化治疗能有效改善重型颅脑损伤合并糖尿病患者的预后,降低ICU内并发症的发生率。     

The influence of insulin infusion on the metabolism of amyloid β peptides in plasma

BackgroundAccumulating body of evidence suggests pathophysiologic links between Alzheimer’s disease and diabetes mellitus (DM). For example, the two crucial peptides playing a role in both degenerative disorders, amyloid β (Aβ) and insulin, are metabolized by the same enzyme, insulin degrading enzyme. Euglycemic hyperinsulinemic clamp is a method of estimating insulin sensitivity, based on the assumption that during steady-state hyperinsulinemic euglycemia, glucose infusion rate equals tissue glucose uptake, that is, the higher the glucose infusion rate, the higher the insulin sensitivity.ObjectiveThe aim of this study was to analyze the influence of insulin on the plasma concentrations of Aβ peptides.MethodsBlood samples were collected from 20 healthy young male volunteers before insulin infusion (clamp) and then at 120 and 360 minutes. In the second protocol, insulin was accompanied by Intralipid, which is mainly a mixture of triacylglycerols, and heparin, given as an activator of lipoprotein lipase, inducing insulin resistance. Analyses of plasma Aβ1-42, Aβx-42, Aβ1-40, and Aβx-40 were performed with multiplexing technology. Furthermore, concentrations of the Aβ peptides in healthy persons were compared with those in 16 type 1 DM patients receiving chronic insulin therapy.ResultsWhen applied alone (i.e., without Intralipid), insulin infusion increased concentrations of Aβ42 (full length and N-terminally shortened) but not of Aβ40. When combined with Intralipid, infusion of insulin resulted in increased concentrations of all peptides (nonsignificant tendency in case of Aβx-40). We did not observe differences between Aβ peptide concentrations in healthy subjects and those in type 1 DM patients.ConclusionInfusion of insulin in nonphysiologic high doses increases plasma concentrations of Aβ peptides; in case of Aβ40, only when applied together with Intralipid, which perhaps might be explained by hypothetical shift of insulin degrading enzyme activity from degradation of Aβ peptides to the degradation of insulin.     

胰岛素强化治疗应用于ICU获得性肌无力的临床疗效观察

目的观察胰岛素强化治疗ICU获得性肌无力患者的临床疗效。方法 52例获得性肌无力患者随机分为对照组和研究组各26例。对照组给予常规胰岛素治疗,血糖控制在180~200mg/dl,研究组给予强化胰岛素治疗,血糖控制在80~110mg/dl,其余治疗同对照组。记录并比较2组原发疾病后第1、2、3月英国医学研究委员会(MRC)肌力评分、改良Barthel指数评分(BMI)及2组机械通气时间、ICU住院时间及总住院时间。结果研究组不同测量时间点MRC、BMI评分均高于对照组(P均0.05),机械通气时间、ICU住院时间及总住院时间均少于对照组(P均0.05)。结论强化胰岛素治疗可控制ICUAW的发生及发展,改善患者预后。     

Delayed-onset encephalopathy and coma in acute organophosphate poisoning in humans

The objective of the study was to describe the clinical characteristics and course of delayed-onset organophosphate (OP) poisoning. In our clinical experience, we have noticed patients with onset of deep coma 4-7 days after hospital admission, clinical features that have not been previously described. We set up a prospective observational study over 1 year to formally characterize this observation. Thirty-five patients admitted to the intensive care unit (ICU) with severe OP poisoning and treated with atropine and supportive therapy were followed up. Oximes were not administered. Three patients developed delayed-onset coma after presenting with normal or near normal Glasgow coma score (GCS). They developed altered conscious state rapidly progressing to deep coma, 5.0+/-1.0 (mean+/-S.D.) days after OP ingestion. The GCS persisted at 2T for 4.3+/-2.1 days despite the cessation of sedative drugs at the onset of coma. During this period, the patients had miosed non-reacting pupils and no clinically detectable cortical or brainstem activity. Computed tomography of the brain and cerebrospinal fluid analysis were normal. Electroencephalogram showed bihemispheric slow wave disturbances. Two patients required atropine during this period to maintain heart rate and reduce secretions. In all three patients, no metabolic, infective or non-infective cause of altered conscious state was identified. With supportive therapy the GCS improved to 10T in 8.0+/-2.0 days. All patients survived to hospital discharge. Three other patients who developed a reduction in GCS (3T-7T) by 4.7+/-1.2 days but not progressing to coma and recovering (GCS 10T) in 3.3+/-0.6 days may have manifested delayed-onset encephalopathy. Delayed-onset coma appears to have a distinct clinical profile and course with complete resolution of symptoms with supportive therapy. Although persistent cholinesterase inhibition is likely to have contributed to the manifestations, the mechanism of coma and encephalopathy need to be explored in further trials. The good outcomes in these patients suggest that therapy should not be limited in OP-poisoned patients developing profound coma or encephalopathy during hospitalization.     

Modifications in the insulin treatment of Schizophrenia

Summary A form of insulin therapy is presented, modified to include the use of metrazol simultaneously with insulin in those patients resistive to the insulin treatment of Sakel. It is well to emphasize here that each first receives insulin therapy but that only unresponsive cases are subjected to the combined treatment.This modified technique emphasizes the importance of the role of the epileptiform seizure in the treatment of both acute and chronic cases of schizophrenia.Results in our series of nine cases which showed no improvement following insulin treatment showed that three patients were definitely improved, one sufficiently to warrant parole.     

Serum insulin and leptin levels in valproate-associated obesity

PURPOSE: Weight gain is an important adverse effect of valproate (VPA) therapy, and it is associated with hyperinsulinemia and hyperandrogenism in women with epilepsy. Leptin is considered a signaling factor regulating body weight and energy metabolism. In human subjects, obesity is in general associated with elevated serum leptin levels, suggesting decreased sensitivity to leptin. The present study aimed at evaluating the role of insulin and leptin in VPA-related obesity. METHODS: Body mass index (BMI) was calculated, and serum insulin and leptin levels were measured in 81 patients with epilepsy taking VPA and in 51 healthy control subjects. RESULTS: Forty (49%) of the patients taking VPA and 25 (49%) of the control subjects were obese. The mean insulin levels were higher in VPA-treated patients than in the control subjects despite similar BMI values, when all subjects were included in the comparison. Both obese male and female patients taking VPA had higher serum insulin levels than the respective control subjects with similar BMI values. Serum insulin levels also were higher in lean male and lean female patients compared with the lean control subjects of same sex. Serum leptin levels did not differ between the VPA-treated patients and the control subjects. CONCLUSIONS: Both obese and lean patients taking VPA for epilepsy have hyperinsulinemia, suggesting development of insulin resistance. This may be one of the factors leading to weight gain during VPA treatment. However, the results of the present study do not suggest an independent role for leptin in the pathogenesis of VPA-related obesity.     

Relative insulin insensitivity and cortisol secretion in depressed patients

Relative insulin insensitivity occurs in a substantial portion of patients with major endogenous depressions, and about half such cases also hypersecrete cortisol in the afternoon and evening. This study assessed the relation between these two abnormalities in 16 patients with major endogenous depression. Over several days, insulin tolerance tests (ITTs) were performed in the morning and evening, and measures of cortisol secretion taken: plasma cortisol at 0800, 1600, and 2300 hours, both before and after dexamethasone; baseline cortisol before ITTs; and mean 24-hour plasma cortisol concentrations (in 10 cases). After clinical recovery, some of these patients had repeat ITTs (n=10) and repeat predexamethasone and postdexamethasone cortisol assessments (n=9). Additionally two control groups of 15 normal subjects and of 12 schizophrenic patients received morning ITTs. None of the control subjects manifested insulin insensitivity. However, during illness, 8 of the 16 depressed patients manifested relative insulin insensitivity (glucose drop <50%, glucose nadir > 50 mg/dl); compared to the insulin responsive depressed group, the insensitive group had insignificantly greater afternoon and evening cortisol secretion by nearly all indices. After clinical recovery, hypoglycemic response for the entire group was significantly greater than during illness; this improvement was accounted for by the increased insulin responsivity of the previously insulin resistant subgroup. There was also substantial plasma cortisol reduction in the previously insulin resistant group after clinical recovery, but not in the insulin sensitive group.     

Olanzapine induces insulin resistance: results from a prospective study

BACKGROUND: The aim of this study was to compare glucose metabolism in patients with schizophrenia receiving olanzapine with that in control subjects. METHOD: We conducted a prospective, controlled, open study comparing body weight, fat mass, and indices of insulin resistance/ sensitivity in 10 olanzapine-treated patients with ICD-10 schizophrenia (olanzapine dose range, 7.5-20 mg/day) with those of a group of 10 mentally and physically healthy volunteers. Weight, fat mass, and indices of insulin resistance/sensitivity were assessed over individual 8-week observation periods from November 1997 to October 1999. RESULTS: Fasting serum glucose and fasting serum insulin increased significantly in the olanzapine-treated patients (p =.008 for glucose and p =.006 for insulin). The homeostasis model assessment (HOMA) index for beta cell function did not change significantly in the olanzapine-treated patients, whereas the HOMA index for insulin resistance did increase (p =.006). In the control group, these parameters were stable. A significant increase in body weight (p =.001) and body fat (p =.004) was seen in patients treated with olanzapine, while the control group showed no significant changes. CONCLUSION: This study indicates that the disturbances in glucose homeostasis during antipsychotic treatment with olanzapine are mainly due to insulin resistance. However, beta cell function remains unaltered in olanzapine-treated patients. We conclude that treatment with some second-generation antipsychotic drugs may lead to insulin resistance.     

Intranasal insulin ameliorates neurological impairment after intracerebral hemorrhage in mice

In Alzheimer’s disease and ischemic stroke,intranasal insulin can act as a neuroprotective agent.However,whether intranasal insulin has a neuroprotective effect in intracerebral hemorrhage and its potential mechanisms remain poorly understood.In this study,a mouse model of autologous blood-induced intracerebral hemorrhage was treated with 0.5,1,or 2 IU insulin via intranasal delivery,twice per day,until 24 or 72 hours after surgery.Compared with saline treatment,1 IU intranasal insulin treatment significantly reduced hematoma volume and brain edema after cerebral hemorrhage,decreased blood-brain barrier permeability and neuronal degeneration damage,reduced neurobehavioral deficits,and improved the survival rate of mice.Expression levels of p-AKT and p-GSK3βwere significantly increased in the perihematoma tissues after intranasal insulin therapy.Our findings suggest that intranasal insulin therapy can protect the neurological function of mice after intracerebral hemorrhage through the AKT/GSK3βsignaling pathway.The study was approved by the Ethics Committee of the North Sichuan Medical College of China(approval No.NSMC(A)2019(01))on January 7,2019.     

Phenytoin-induced improvement in muscle cramping and insulin action in three patients with the syndrome of insulin resistance, acanthosis nigricans, and acral hypertrophy

Phenytoin sodium has been used to treat muscle cramps of diverse causes, and is known to increase insulin sensitivity during long-term use. We have previously described a syndrome of insulin resistance, acanthosis nigricans, and acral hypertrophy with continual muscle cramping. The effect of 300 mg/d of phenytoin (Dilantin) on muscle cramping and carbohydrate economy was studied in three affected patients and four control subjects. Oral glucose tolerance tests, euglycemic insulin infusion studies, and monocyte insulin binding tests were conducted before and after phenytoin administration. All three patients had notable improvement in muscle cramps. In response to phenytoin, metabolic improvements were variable, with improvement characteristically better in patients with less severe baseline metabolic abnormalities. Patient 1, with the mildest degree of glucose intolerance, had decreased fasting insulin and blood glucose levels, improved glucose tolerance, and insulin-mediated glucose disposal, associated with an increase in monocyte insulin receptors. Patient 2 had reduced fasting plasma glucose and insulin levels and improved oral glucose tolerance, suggesting a beneficial effect on carbohydrate metabolism. Patient 3, with the most severely impaired carbohydrate economy, showed no metabolic improvement despite marked lessening of muscle pain. These clinical characteristics were unaffected in control subjects. We conclude that phenytoin is of value in the therapy of muscle cramps and glucose intolerance in patients with this syndrome.