Insulin resistance after oral glucose tolerance testing in patients with major depression

An association between affective disorders and alterations in glucose utilization has been recognized. The authors administered a 5-hour oral glucose tolerance test (GTT) to 28 depressed patients and 21 healthy volunteer control subjects and measured serum glucose as well as plasma insulin and glucagon responses. Depressed patients demonstrated significantly higher basal glucose levels, greater cumulative glucose responses after the GTT, and larger cumulative insulin responses after the GTT than control subjects. Values for cumulative glucagon did not significantly differ between groups. These findings indicate the presence of a functional state of insulin resistance during major depressive illness and suggest the presence of a more generalized biological disturbance in some depressed patients.     

Eating attitudes and glucose tolerance in anorexia nervosa patients at 8-year followup compared to control subjects

This study analyzed eating attitudes and plasma glucose, insulin, unesterified fatty acid (FFA), human growth hormone (GH), and cortisol responses to an oral (100 g) glucose load in 26 female anorexia nervosa patients at an 8-year outcome evaluation in comparison to 14 age-matched female control subjects. Recovered patients who were of normal body weight and had cyclical menstruation (n = 19) showed glucose tolerance curves and insulin, cortisol, and GH responses that were indistinguishable from those of normal subjects, although patients tended to be more diet-conscious than controls and showed elevated fasting FFA levels. Two of 19 recovered patients met criteria for impaired glucose tolerance. Nonrecovered patients (n = 7) showed abnormal eating attitudes at an average underweight of 20% with persistent amenorrhea or oligomenorrhea. They had high fasting FFA plasma levels, significantly greater than normal rises in plasma glucose, a significant delay in serum insulin secretion, higher mean glucose levels before and after controlling for amount of exercise, and paradoxical release of GH. One of seven patients met criteria for diabetes mellitus and two of seven had impaired glucose tolerance. The findings suggest that fasting plasma FFA levels may reflect patients' eating and exercise habits more accurately than their verbal or written reports.     

Abnormal insulin secretion in amyotrophic lateral sclerosis

Plasma glucose and insulin (IRI) values during a 50-g oral glucose tolerance test were measured in patients with amyotrophic lateral sclerosis (ALS). Blood sugar curves were abnormal in 7 out of 18 patients in whom glucose tolerance tests were performed, and mean values of plasma glucose levels at 30, 60 and 120 min after glucose loading in the patients were significantly higher than those in control subjects. All cases with generalized muscle atrophy showed abnormal glucose tolerance except for 2 cases who showed borderline response, while in cases with localized atrophy, all but one borderline case demonstrated normal response. IRI response in patients with ALS was abnormal in 11 out of 14 cases, and the mean value at 30 min after glucose administration in the patients was significantly lower than that in control subjects; it was abnormal even in patients who did not have generalized muscle atrophy and showed normal glucose tolerance. The results suggest that abnormal glucose metabolism in ALS is primarily based on the impairment of pancreatic insulin secretion and that the addition of generalized muscle atrophy to the above factor results in apparently abnormal glucose utilization.     

Abnormal growth hormone and cortisol, but not thyroid-stimulating hormone, responses to an intravenous glucose tolerance test in normal-weight, bulimic women

Abnormal growth hormone (GH) and adrenocorticotropic hormone (ACTH)/cortisol secretory patterns in response to a glucose load have been observed in underweight anorectic women. The present study was performed in an attempt to establish whether changes in the hypothalamic/pituitary sensitivity to hyperglycemia occur in bulimia in the absence of weight disturbance. Therefore, serum GH, plasma cortisol, and plasma insulin concentrations were measured in eight women with normal weight bulimia and in eight normal women during an intravenous glucose (0.33 g/kg as an bolus) tolerance test (IGTT). In addition, since abnormal pituitary hormone responses to a glucose load might reflect alterations in somatostatin (SRIH) release, TSH secretion also was measured, in view of its sensitivity to SRIH inhibition.

Both GH and cortisol levels progressively and significantly declined during IGTT in the normal subjects. In the bulimic women, cortisol levels remained unchanged, whereas GH concentrations rose significantly after glucose injection. Plasma cortisol and serum GH levels were significantly higher in the bulimic than in the control subjects. No significant differences between groups were observed in hyperglycemia-induced insulin increments or in TSH decrements.

These data indicate that an altered sensitivity to hyperglycemia affects the hypothalamic/pituitary centers controlling the secretion of the counterregulatory hormones GH and ACTH/cortisol in bulimia nervosa. The lack of a simultaneous change in the TSH secretory pattern argues against a possible involvement of SRIH in the pathophysiology of this disorder.     

Changes in anterior pituitary function during ACTH therapy of patients with infantile spasms

Serum cortisol, prolactin (PRL), TSH, GH, LH and FSH levels were measured before and immediately after daily ACTH-Z therapy (0.01 mg/kg/day, 1-2 weeks) for 5 patients with infantile spasms and one patient with myoclonus epilepsy. Total number of ACTH-Z therapy were 8 times, and all patients became seizure free after ACTH-Z therapy. In 6 occasions, TRH, LH-RH and insulin tolerance tests were performed before and after daily ACTH-Z therapy. Serum cortisol levels were significantly increased after daily ACTH-Z therapy but all other hormone levels were significantly decreased. In TRH and LH-RH tolerance tests, peak levels and increments of PRL, LH and FSH were significantly decreased after daily ACTH-Z therapy and those of TSH were mildly decreased. In one case insulin tolerance test revealed an adequate decrease of blood glucose before and after ACTH-Z therapy, and there was a poor GH response after ACTH-Z therapy. Daily ACTH-Z therapy was thought to suppress secretion of anterior pituitary hormones.     

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.     

Glucose metabolism alterations in Friedreich's ataxia

We have characterized the abnormalities of glucose metabolism associated with Friedreich's ataxia (FA) by studying plasma glucose, insulin, growth hormone (GH), and glucagon before and after an oral glucose tolerance test (OGTT), an IV glucose load, and an IV arginine load, in 21 patients and in controls. Twelve patients were normotolerant (NT) to glucose, five glucose-intolerant (IT), and four diabetic (DM). Insulin secretion of IT patients was increased and delayed during OGTT. Interestingly, the insulin release during arginine load was significantly decreased in NT and IT as well as in DM patients. The GH response to OGTT was altered in IT patients. Plasma glucagon after an arginine load was significantly higher in patients than in controls. The results indicate that FA is associated with insulin resistance, beta-cell deficiency, and type I diabetes. These alterations might be genetically linked or metabolically related to the primary defect in FA. Their interplay or independent effects are responsible for abnormalities of glucose metabolism in FA.     

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.     

Growth hormone responses to growth hormone-releasing hormone, clonidine and insulin-induced hypoglycemia in normal weight bulimic women

The growth hormone (GH) responses to GH-releasing hormone (GHRH; 1 microgram/kg BW in an i.v. bolus), clonidine (150 micrograms in a single oral dose) and insulin (0.15 IU/kg BW in an i.v. bolus) induced hypoglycemia were evaluated in 7 normal weight bulimic women with regular menstrual cycles and in 7 age- and weight-matched normal women. In addition, the effect of thyrotropin-releasing hormone (TRH; 200 micrograms in an i.v. bolus) on serum thyroid-stimulating hormone (TSH) and GH levels was measured in the same subjects. Tests were carried out in random order on the 22nd days of the following menstrual cycles. A control test with the i.v. administration of normal saline instead of drugs was carried out 2 days after the TRH test. Basal GH levels were significantly higher in bulimic women than in normal controls; despite higher GH levels, bulimic women showed normal circulating concentrations of somatomedin-C (Sm-C). Serum GH levels remained unmodified during the control test. In contrast, the administration of GHRH, clonidine or insulin induced significant GH responses in all subjects. Bulimic and normal women showed comparable responses after GHRH, clonidine or hypoglycemia. The hypoglycemic response to insulin was similar in bulimic and control subjects. The administration of TRH was unable to increase the circulating levels of GH in the normal controls, whereas it significantly increased GH concentrations in 5 of 7 bulimic women.(ABSTRACT TRUNCATED AT 250 WORDS)     

THE EFFECTS OF TOXIC AND NON-TOXIC SERUM PHENYTOIN LEVELS ON CARBOHYDRATE TOLERANCE AND INSULIN LEVELS

The effect of toxic and non-toxic phenytoin levels on carbohydrate tolerance and insulin levels was studied in 18 patients with epilepsy and 17 control subjects. Toxic levels were defined as a serum level greater than 20 μg/ml. Toxic levels occurred in 11 patients and non-toxic levels in seven patients. Blood glucose and insulin levels were measured at 30-min intervals for a period of 3 h following the ingestion of 50 g glucose. Blood glucose levels were measured by the ferricyanide method, and serum insulin levels by immunoassay of insulin with insulin antibody precipitate. Serum phenytoin levels were measured by gas liquid chromatography. The insulin profiles were the same for all three groups, but there was a significant delay in reaching peak glucose concentrations in patients with toxic levels of phenytoin. It was therefore confirmed that non-toxic levels of phenytoin do not affect carbohydrate tolerance or insulin levels when phenytoin is used in the routine treatment of epilepsy, and it has also been shown that toxic levels of phenytoin do not affect carbohydrate tolerance when the high levels are detected at an early stage.     

Hormone and metabolite plasma levels after oral glucose in bulimia and healthy controls

Bulimia patients claim to crave sweets and since as clinical evidence suggests that the food consumed during eating binges often contains large amounts of carbohydrates, hormones involved in carbohydrate metabolism might be affected in bulimia. We therefore performed a 4-hr glucose tolerance test (GTT), using 100 g oral glucose and inquired about attitudes toward sweets. Thirteen female patients, with a mean age of 23.3 years, who had had bulimia from 3 to 7 years but whose binge-eating/vomiting behavior was largely controlled at the time of testing, were compared to 14 age-matched healthy female controls with a mean age of 24.4 years. All bulimic patients and most controls had liked sweets as children and still liked sweets. Significantly more bulimic patients than controls stated they overate on sweets and avoided sweets. Glucose utilization and the insulin, glucagon, growth hormone (GH), and pancreatic polypeptide (PP) response curves in the bulimic patients were within the normal range. Fasting plasma levels of glucose, insulin, glucagon, GH, cortisol, free fatty acids (FFA), and PP were not different from controls. There was a trend in bulimic patients to have lower plasma FFA levels and higher plasma cortisol levels during the GTT than controls. The findings suggest that, given body weight maintenance and adequate nutrition, patients with bulimia nervosa have normal glucose tolerance and normal hormonal responses following an oral glucose load.     

Neurotransmitter metabolites and endocrine responses in depression

1. Urinary 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), 3–4-dihydroxyphenylethylene-glycol (DHPG), 5-hydroxyindoleacetic acid (5-HIAA), plasma thyroid stimulating hormone (TSH), prolactin (PRL) and growth hormone (GH) were measured before and after the injection of thyrotropin releasing hormone (TRH) in healthy subjects and depressed patients with primary affective disorder.

2. The TSH response to TRH did not differ in depressed compared with control subjects. A trend (.05 < p < .10) toward a lower PRL response appeared in male depressed compared with male control subjects. GH levels did not consistently change after TRH.

3. In all subjects the TSH response correlated positively with pre- and post-TRH urinary MHPG. The PRL response correlated negatively with pre-TRH urinary 5-HIAA. Pre-TRH daytime urinary 5-HIAA levels were elevated in depressed subjects.     

The metabolic and hormonal response to glucagon. Part 1. Normal subjects.

Significant increases in mean plasma noradrenaline levels were observed 30-60 min and 150-180 min after a subcutaneous injection of 1 mg glucagon. The first peak coincided with the maximum blood glucose and plasma insulin levels and the second peak occurred after plasma growth hormone (GH) and cortisol levels had begun to rise. The first plasma noradrenaline peak may be important in inhibiting further insulin secretion. There was no evidence that glucagon stimulates adrenaline secretion in normal human subjects. It was also confirmed that there are significant increases in the levels of glucose, insulin, GH and cortisol and a significant decrease in FFA levels following subcutaneous injection of glucagon in normal human subjects.     

The endocrine abnormalities of depressive patients]

In the present study, the levels of the baseline cortisol, thyrotropin (TSH), triiodothyronine (T3), thyroxine (T4) and growth hormone (GH) were determined in 64 depressive patients, 17 patients with other depressive disorders and 19 normal controls. Meanwhile, dexamethasone suppression test (DST) and insulin tolerance test (ITT) were conducted. The baseline cortisol level at 23:00 in the depressive group (8.12 +/- 5.55 micrograms/dl) was significantly higher than that in the normal control group (4.80 +/- 2.10 micrograms/dl), and DST nonsuppression ratio in the depressive group (14.5%) was significantly higher than those in the other two groups (0%). There were not significantly differences in the levels of the baseline TSH, T3 and T4 between the three groups. There were not significantly differences in the baseline GH level between the three groups, but GH level in the depressive group at 90 min. after infusing insulin was significantly lower than that in the normal control group. The results showed the HPA axis hyperactivity, normal thyroid function and blunted GH response to insulin-induced hypoglycemia at 90 min. in ITT in the depressive patients.     

Neuroendocrine and amine studies in affective illness.

(1) There are limitations to some of these studies because of the small number of patients involved, but our data suggest that maximal Growth Hormone (GH) levels after induced hypoglycemia were lower in depressed patients than in control subjects. (2) Manic patients showed low GH peaks during the Insulin Tolerance Test (ITT), and furthermore urinary 3-methoxy-4-hydroxyphenylene glycol (MHPG) excretion rates in mania were indistinguishable from normals but higher than in depressed patients. (3) The apomorphine-induced GH response was essentially normal in affective disorder patients, while acute schizophrenic patients showed hypersensitivity of postsynaptic dopamine receptors. (4) Confirming previous studies by Maas et al. (1968, 1972), patients with depressive illness were found to have signicantly lower urinary MHPG excretion, whereas borderline patients with depressive symptomatology had MHPG values similar to control subjects.     

Abnormalities in glucose regulation during antipsychotic treatment of schizophrenia

BACKGROUND: Hyperglycemia and type 2 diabetes mellitus are more common in schizophrenia than in the general population. Glucoregulatory abnormalities have also been associated with the use of antipsychotic medications themselves. While antipsychotics may increase adiposity, which can decrease insulin sensitivity, disease- and medication-related differences in glucose regulation might also occur independent of differences in adiposity. METHODS: Modified oral glucose tolerance tests were performed in schizophrenic patients (n = 48) receiving clozapine, olanzapine, risperidone, or typical antipsychotics, and untreated healthy control subjects (n = 31), excluding subjects with diabetes and matching groups for adiposity and age. Plasma was sampled at 0 (fasting), 15, 45, and 75 minutes after glucose load. RESULTS: Significant time x treatment group interactions were detected for plasma glucose (F(12,222) = 4.89, P<.001) and insulin (F(12,171) = 2.10, P =.02) levels, with significant effects of treatment group on plasma glucose level at all time points. Olanzapine-treated patients had significant (1.0-1.5 SDs) glucose elevations at all time points, in comparison with patients receiving typical antipsychotics as well as untreated healthy control subjects. Clozapine-treated patients had significant (1.0-1.5 SDs) glucose elevations at fasting and 75 minutes after load, again in comparison with patients receiving typical antipsychotics and untreated control subjects. Risperidone-treated patients had elevations in fasting and postload glucose levels, but only in comparison with untreated healthy control subjects. No differences in mean plasma glucose level were detected when comparing risperidone-treated vs typical antipsychotic-treated patients and when comparing typical antipsychotic-treated patients vs untreated control subjects. CONCLUSION: Antipsychotic treatment of nondiabetic patients with schizophrenia can be associated with adverse effects on glucose regulation, which can vary in severity independent of adiposity and potentially increase long-term cardiovascular risk.     

Glucose tolerance in amyotrophic lateral sclerosis

Blood glucose and plasma insulin during an oral glucose tolerance test were determined in 21 patients with amyotrophic lateral sclerosis and in 10 control patients matched for age, obesity and physical activity. In addition, 125I-insulin binding to circulating erythrocytes were studied in a subgroup of 4 ALS patients and 8 controls. Both impaired glucose tolerance and diabetes mellitus were evenly distributed between the study groups, and no difference in mean blood glucose levels during the OGTT was found between ALS and control patients. Fasting plasma immunoreactive insulin concentration was significantly higher in ALS patients as compared to controls, but plasma IRI increments to the glycemic stimulus were similar in the 2 groups. The number of insulin binding sites per cell appeared lower in patients with ALS, but the difference in receptor concentration was not statistically significant. In addition, the specific bound fraction of 125I-insulin showed no difference between ALS and control patients. In conclusion, we were unable to demonstrate any marked deterioration of glucose tolerance or increase in insulin resistance in patients with ALS.     

Endocrine functions in Huntington''s disease: A two-and-a-half years follow-up study

An oral glucose tolerance test (OGTT) was performed in 1985 in 10 patients with Huntington's disease (HD), while 10 healthy age-matched volunteers served as controls. Two-and-a-half years later, in 1988, 8 of the original 10 patients were reinvestigated. Apart from glucose, insulin and growth hormone (sampled at 30 min intervals) the following parameters of endocrine function were assessed: C-peptide (at times 0 and 60 min), glycosylated haemoglobin (HbAlc), somatomedin-C, and basal prolactin. In 1985 one female patient was considered to have impaired glucose tolerance, and this same patient, as well as another male patient, had a paradoxical rise in GH secretion. None of the other measurements of endocrine function differed significantly from control. In 1988 the HD patients had clinically deteriorated significantly, as measured by the Shoulson and Fahn Scale. Six of them completed a repeat OGTT. Of these 6, the same female as in 1985 showed impaired glucose tolerance. Now none of the participants had a paradoxical GH rise. The HD patients did not show any deterioration of the parameters of glucose metabolism, nor of GH secretion. The basal prolactin level, however, decreased significantly in these 2.5 years, from 9.3 ± 3.2 μg/l to 6.1 ± 3.0 μg/l (P < 0.01).     

Growth hormone-releasing factor stimulation test in depression

The authors administered the growth hormone-releasing factor (GRF) stimulation test to 19 patients with major depression and 19 age- and sex-matched control subjects to test the hypothesis that a blunted growth hormone (GH) response to clonidine reflects a central alpha 2-adrenergic receptor subsensitivity in depression. GH response to GRF was significantly higher in patients with depression than in control subjects. This group difference was mainly attributable to three of the 19 depressed patients who exhibited markedly high GH responses to GRF. These results suggest that the blunted GH response to clonidine seen in patients with depression is not due to a pituitary defect in GH secretion.     

Impaired fasting glucose tolerance in first-episode,drug-naive patients with schizophrenia

OBJECTIVE: This study examined the prevalence of impaired fasting glucose tolerance in first-episode, drug-naive patients with schizophrenia. METHOD: In this cross-sectional study, fasting plasma levels of glucose, insulin, lipids, and cortisol were measured in 15 male and 11 female hospitalized Caucasian patients with DSM-IV schizophrenia (mean age=33.6 years) and age- and sex-matched healthy comparison subjects. The patients and comparison subjects were also matched in terms of various life-style and anthropometric measures. RESULTS: More than 15% of the drug-naive, first-episode patients with schizophrenia had impaired fasting glucose tolerance, compared to none of the healthy volunteers. Compared with the healthy subjects, the patients with schizophrenia had significantly higher fasting plasma levels of glucose (mean=88.2 mg/dl, SD=5.4, for the healthy subjects versus mean=95.8 mg/dl, SD=16.9, for the patients), insulin (mean=7.7 micro u/ml, SD=3.7, versus mean=9.8 micro u/ml, SD=3.9), and cortisol (mean=303.2 nmol/liter, SD=10.5, versus mean=499.4 nmol/liter, SD=161.4) and were more insulin resistant, as measured with homeostasis model assessment (mean=1.7, SD=0.7, for the healthy subjects versus mean=2.3, SD=1.0, for the patients). CONCLUSIONS: First-episode, drug-naive patients with schizophrenia have impaired fasting glucose tolerance and are more insulin resistant and have higher levels of plasma glucose, insulin, and cortisol than healthy comparison subjects.