Trimester-specific reference intervals for thyroid function parameters in pregnant Caucasian women using Roche platforms: a prospective study.

BACKGROUND: Standard thyroid function parameters reference intervals (RI) are unsuitable during pregnancy, potentially resulting in incongruous treatments that may cause adverse effects on pregnancy outcomes. We aimed at defining trimester-specific TSH, FT4 and FT3 RI, using samples longitudinally collected from healthy Caucasian women. MATERIALS AND METHODS: Blood samples from 150 healthy Caucasian women, who had a physiological gestation and a healthy newborn at term, were collected in each trimester and at around six months post-partum. They showed mild iodine deficiency. After excluding women with overt TSH abnormalities (> 10 mU/L) and/or TPO antibodies, data from 139 pregnant women were analyzed by means of widely used Roche platforms, and TSH, FT4 and FT3 trimester-specific RI were calculated. Post-partum data were available for 55 subjects. RESULTS: Serum TSH RI were 0.34-3.81 mU/L in the first trimester, and changed slightly to 0.68-4.07 U/L and 0.63-4.00 mU/L in the second and third trimester, respectively. Conversely, both FT4 and FT3 concentrations progressively decreased during pregnancy, the median values in the third trimester being 14.8% and 13.2% lower, respectively, than in the first trimester. Thyroid function parameters in the first trimester were similar to those measured after the end of pregnancy. CONCLUSIONS: This study calculates trimester-specific RI for thyroid function parameters in pregnancy, and proposes the reference limits that should be adopted when using Roche platforms in Caucasian women.

Serum HMGB1 levels are independently associated with glucose clamp-derived measures of insulin resistance in women with PCOS.

PURPOSE: PCOS is associated with low grade inflammation which could play a role in insulin resistance and ovarian dysfunction. Preliminary findings suggested that serum levels of HMGB1, a cytokine involved in inflammation, might be altered in women with PCOS. Primary aim of this study was to assess whether HMGB1 serum concentrations are associated with PCOS and with the state of insulin resistance of these women. METHODS: Sixty women with PCOS, selected to have a similar proportion of subjects with altered or normal insulin sensitivity, and 29 healthy controls were studied. Serum HMGB1 levels were compared in subgroups of PCOS women and controls. In PCOS women, insulin sensitivity was assessed by the glucose clamp technique and HMGB1 was measured at baseline and after acute hyperinsulinemia. RESULTS: HMGB1 levels were similar in women with PCOS and controls and no elements used for diagnosing PCOS were associated with serum HMGB1. However, HMGB1 concentrations were higher in insulin-resistant vs insulin-sensitive PCOS women (p = 0.017), and inversely associated with insulin-induced total and non-oxidative glucose metabolism. In both subgroups of PCOS women, serum HMBG1 levels significantly increased after acute hyperinsulinemia. CONCLUSIONS: These data suggest that HMGB1 levels are not associated with PCOS per se, but with insulin resistance. Further research should establish the underlying nature of this relationship, and whether this protein might play a role in the metabolic complications of PCOS.

The physiological sonographic features of the ovary in healthy subjects: a joint systematic review and meta-analysis by the Italian Society of Gynecology and Obstetrics (SIGO) and the Italian Society of Endocrinology (SIE).

PURPOSE: There is a lack of uniformity in the definition of normal ovary ultrasound parameters. Our aim was to summarize and meta-analyze the evidence on the topic. Full-text English articles published through December 31, 2020 were retrieved via MEDLINE and Embase. Data available for meta-analysis included: ovarian follicular count, ovarian volume, and ovarian Pulsatility Index (PI) assessed by Doppler ultrasound. METHODS: Cohort, cross-sectional, prospective studies with a single or double arm were considered eligible. Interventional studies were included when providing baseline data. Both studies on pre- and post-menopausal women were screened; however, data on menopausal women were not sufficient to perform a meta-analysis. Studies on pre-pubertal girls were considered separately. Eighty-one papers were included in the meta-analysis. RESULTS: The mean ovarian volume was 6.11 [5.81-6.42] ml in healthy women in reproductive age (5.81-6.42) and 1.67 ml [1.02-2.32] in pre-pubertal girls. In reproductive age, the mean follicular count was 8.04 [7.26-8.82] when calculated in the whole ovary and 5.88 [5.20-6.56] in an ovarian section, and the mean ovarian PI was 1.86 [1.35-2.37]. Age and the frequency of the transducers partly modulated these values. In particular, the 25-30-year group showed the higher mean follicular count (9.27 [7.71-10.82]), followed by a progressive age-related reduction (5.67 [2.23-9.12] in fertile women > 35 years). A significant difference in follicular count was also found according to the transducer's upper MHz limit. CONCLUSION: Our findings provide a significant input to improve the interpretation and diagnostic accuracy of ovarian ultrasound parameters in different physiological and pathological settings.

Insulin resistance and PCOS: chicken or egg?

PCOS is a common and heterogeneous endocrine disorder in women of reproductive age, frequently associated with metabolic abnormalities. It was estimated that about 75% of these subjects have an impairment of insulin action, as measured by gold standard methods. While the relationship between insulin resistance and PCOS is consistently shown by a number of studies, the mechanisms underlying its primary origin still remains an unsolved issue. Insulin resistance and the associated hyperinsulinemia can induce both the endocrine and reproductive traits of PCOS. However, androgen excess, in turn, can impair insulin action, directly and/or through several changes occurring in different tissues. Body fat excess, which is another common feature in these women, can contribute to worsening the whole picture. Nevertheless, insulin resistance may also be found in many normal-weight individuals. Endocrine and metabolic abnormalities can develop in different moments, and probably there is fetal programming of these alterations. However, a number of vicious circles, with bidirectional relationships between androgen excess and insulin resistance, and with the contribution of several other factors, make it extremely difficult to understand where this process really originates. This review summarizes available evidence on this topic, in order to better understand the complex relationships linking hyperandrogenism and impaired insulin action in women with PCOS.

Walking for subjects with type 2 diabetes: A systematic review and joint AMD/SID/SISMES evidence-based practical guideline.

AIMS: Regular exercise is considered a cornerstone in the management of type 2 diabetes mellitus (T2DM). It improves glucose control and cardiovascular risk factors, contributes to weight loss, and also improves general well-being, likely playing a role in the prevention of chronic complications of diabetes. However, compliance to exercise recommendations is generally inadequate in subjects with T2DM. Walking is the most ancestral form of physical activity in humans, easily applicable in daily life. It may represent, in many patients, a first simple step towards lifestyle changes. Nevertheless, while most diabetic patients do not engage in any weekly walking, exercise guidelines do not generally detail how to improve its use. The aims of this document are to conduct a systematic review of available literature on walking as a therapeutic tool for people with T2DM, and to provide practical, evidence-based clinical recommendations regarding its utilization in these subjects. DATA SYNTHESIS: Analysis of available RCTs proved that regular walking training, especially when supervised, improves glucose control in subjects with T2DM, with favorable effects also on cardiorespiratory fitness, body weight and blood pressure. Moreover, some recent studies have shown that even short bouts of walking, used for breaking prolonged sitting, can ameliorate glucose profiles in diabetic patients with sedentary behavior. CONCLUSIONS: There is sufficient evidence to recognize that walking is a useful therapeutic tool for people with T2DM. This document discusses theoretical and practical issues for improving its use. This article is co-published in the journals Sport Sciences for Health and Nutrition, Metabolism and Cardiovascular Diseases.

Monitoring exercise intensity in diabetes: applicability of "heart rate-index" to estimate oxygen consumption during aerobic and resistance training.

PURPOSE: Accurate quantification and monitoring of exercise "dose", described by oxygen consumption (VO2), is necessary for exercise prescription and individualization. However, due to the complexity and elevated cost of direct, gold-standard methods, this is rarely done outside research laboratories. Heart rate-index (HRindex) is a new simple method to estimate VO2 in healthy and clinical populations. We tested the performance of HRindex to estimate VO2 in diabetic patients during aerobic (AT) and isotonic training (IT). METHODS: Data from 12 males (age: 64 ± 5 years; BMI: 26 ± 12) with type 2 diabetes were analysed. VO2 and heart rate were measured during one AT and one IT session. Furthermore, VO2 was indirectly estimated based on HRindex. Then, the correspondence between measured and estimated VO2 was evaluated by two-way RM-ANOVA, correlation and Bland-Altman analysis. RESULTS: Estimated average VO2 values during AT (1292 ± 366 ml/min) were not different from (p = 0.243) and highly correlated with (r = 0.87, p < 0.001) the measured values (1369 ± 417 ml/min), with a small bias and imprecision. Conversely during IT, HRindex overestimated VO2 compared to the actual measures (1048 ± 404 vs 667 ± 230 ml/min, p ≤ 0.001) and only a moderate correlation was found between values (r = 0.43, p ≤ 0.001), with a large bias and imprecision. CONCLUSION: VO2 of aerobic exercises can be accurately estimated in diabetes patients using HRindex. During isotonic exercise, this method is not recommended for monitoring metabolic intensity due to large overestimation and imprecision. In aerobic exercise, HRindex offers a simple and valid alternative to the direct VO2 determination and may favour the applicability of time-resolved measures of exercise "dose".

Association of free-living physical activity measures with metabolic phenotypes in type 2 diabetes at the time of diagnosis. The Verona Newly Diagnosed Type 2 Diabetes Study (VNDS).

BACKGROUND AND AIM: Lifestyle is considered a major determinant of risk of type 2 diabetes (T2D). We investigated whether daily physical activity (DPA) is associated with beta-cell function (BF) and/or insulin sensitivity (IS) in patients with T2D at the time of diagnosis. METHODS AND RESULTS: In 41 subjects enrolled in the Verona Newly-Diagnosed Type 2 Diabetes Study we assessed: (1) IS, by euglycaemic insulin clamp; (2) BF, estimated by prolonged-OGTT minimal modeling and expressed as derivative and proportional control; (3) DPA and energy expenditure (EE), assessed over 48-h monitoring by a validated wearable armband system. Study participants (median [IQR]; age: 62 [53-67] years, BMI: 30.8 [26.5-34.3] Kg m-2, HbA1c: 6.7 [6.3-7.3]%; 49.7 [45.4-56.3] mmol/mol) were moderately active (footsteps/day: 7773 [5748-10,927]; DPA≥3MET: 70 [38-125] min/day), but none of them exercised above 6 metabolic equivalents (MET). EE, expressed as EETOT (total daily-EE) and EE≥3MET (EE due to DPA≥3MET) were 2398 [2226-2801] and 364 [238-617] Kcal/day, respectively. IS (M-clamp 630 [371-878] µmol/min/m2) was positively associated with DPA and EE, independent of age, sex and BMI (p < 0.05). Among the DPA and EE parameters assessed, DPA≥3MET and EETOT were independent predictors of IS in multivariable regression analyses, adjusted for age, sex, BMI (R2 = 16%, R2 = 19%, respectively; p < 0.01). None of model-derived components of BF was significantly associated with DPA or accompanying EE. CONCLUSIONS: Our study highlighted moderate levels of DPA and total EE as potential determinants of IS, but not BF, in T2D at the time of diagnosis. Intervention studies are needed to conclusively elucidate the effect of DPA on these features. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. UNIQUE IDENTIFIER: NCT01526720.

Effects of aerobic or resistance exercise training on cardiovascular autonomic function of subjects with type 2 diabetes: A pilot study.

BACKGROUND AND AIMS: Both aerobic (AER) and resistance (RES) training improve metabolic control in patients with type 2 diabetes (T2DM). However, information on the effects of these training modalities on cardiovascular autonomic control is limited. Our aim was to compare the effects of AER and RES training on cardiovascular autonomic function in these subjects. METHODS AND RESULTS: Cardiovascular autonomic control was assessed by Power Spectral Analysis (PSA) of Heart Rate Variability (HRV) and baroreceptors function indexes in 30 subjects with T2DM, randomly assigned to aerobic or resistance training for 4 months. In particular, PSA of HRV measured the Low Frequency (LF) and High Frequency (HF) bands of RR variations, expression of prevalent sympathetic and parasympathetic drive, respectively. Furthermore, we measured the correlation occurring between systolic blood pressure and heart rate during a standardized Valsalva maneuver using two indexes, b2 and b4, considered an expression of baroreceptor sensitivity and peripheral vasoactive adaptations during predominant sympathetic and parasympathetic drive, respectively. After training, the LF/HF ratio, which summarizes the sympatho-vagal balance in HRV control, was similarly decreased in the AER and RES groups. After AER, b2 and b4 significantly improved. After RES, changes of b2 were of borderline significance, whereas changes of b4 did not reach statistical significance. However, comparison of changes in baroreceptor sensitivity indexes between groups did not show statistically significant differences. CONCLUSION: Both aerobic and resistance training improve several indices of the autonomic control of the cardiovascular system in patients with T2DM. Although these improvements seem to occur to a similar extent in both training modalities, some differences cannot be ruled out. CLINICAL TRIAL REGISTRATION NUMBER: NCT01182948, clinicaltrials.gov.

Is cardiorespiratory fitness impaired in PCOS women? A review of the literature.

PURPOSE: Polycystic ovary syndrome (PCOS) is a common and heterogeneous endocrine disorder, affecting 8-12% of reproductive-aged women. Insulin resistance and body fat excess are common features in these subjects. Increased physical activity and diet modifications are the first recommended approach in the management of these women, at least in overweight/obese subjects. Evaluation of cardiorespiratory fitness (CRF) is important in assessing exercise performance and in monitoring the effects of physical exercise interventions. Several studies have shown that CRF may be impaired in metabolic and endocrine disorders. However, there are little data on this issue in PCOS women. The aim of this narrative review is to critically evaluate whether aerobic capacity is altered in PCOS women, focusing on maximal oxygen uptake. METHODS: An updated search of the literature was performed, identifying papers with maximal oxygen consumption measurements in women with PCOS compared to healthy controls. RESULTS: We have identified six studies on this specific topic: four of them showed an alteration of maximal oxygen consumption in PCOS women, whereas two did not. However, taken together these studies suggest that CRF may be strikingly impaired in both normal-weight and overweight/obese subjects with this condition. CONCLUSIONS: Women with PCOS appear to be characterized by a reduced cardiopulmonary fitness. However, further research on this topic is needed. This information may hopefully help clinicians and exercise specialist in planning individualized exercise programs aimed at improving the metabolic and endocrine outcomes in these women.

Low body weight and menstrual dysfunction are common findings in both elite and amateur ballet dancers.

BACKGROUND: Several studies have reported that low body weight and menstrual alterations are very frequent findings in elite dancers, suggesting they could be at risk for associated medical problems. However, it is still largely unknown whether these alterations are also common in the very large number of young amateur dancers. AIM: The aim of this study was to assess whether there is an increased prevalence of menstrual dysfunction also in amateur dancers. MATERIAL/SUBJECTS AND METHODS: Ninety-two professional ballet dancers, 93 non-professional ballet dancers, and 293 (160 sedentary, 133 physically active) control women, ranging in age 14-23 yr, were included in the study. In these subjects, a detailed questionnaire that included questions on weight, height, age at menarche, training profile and menstrual alterations was administered. RESULTS: BMI was lower in both professional and non-professional dancers than in controls. Frequency of menstrual dysfunction was 51%, 34% and 21% in professional dancers, non-professional dancers and controls, respectively (p<0.0001). Amenorrhea was reported by 23% of professional dancers, vs 1-7% in the other groups (p<0.0001). Age at menarche occurred later in professional dancers than in the other groups. Logistic regression analyses showed that menstrual dysfunction was associated with the training profile in professional dancers, and with BMI in non-professional dancers. Age at menarche was associated with menstrual dysfunction in both groups. CONCLUSIONS: This study shows that low body weight and menstrual dysfunction are frequent findings also in amateur ballet dancers.

Accuracy of CGM Systems During Continuous and Interval Exercise in Adults with Type 1 Diabetes.

BACKGROUND: continuous glucose monitoring systems (CGMs) play an important role in the management of T1D, but their accuracy may reduce during rapid glucose excursions. The aim of study was to assess the accuracy of recent rt-CGMs available in Italy, in subjects with T1D during 2 sessions of physical activity: moderate continuous (CON) and interval exercise (IE). METHOD: we recruited 22 patients with T1D, on CSII associated or integrated with a CGM, to which a second different sensor was applied. Data recorded by CGMs were compared with the corresponding plasma glucose (PG) values, measured every 5 minutes with the glucose analyzer. To assess the accuracy of the CGMs, we evaluated the Sensor Bias (SB), the Mean Absolute Relative Difference (MARD) and the Clarke error grid (CEG). RESULTS: a total of 2355 plasma-sensor glucose paired points were collected. Both average plasma and interstitial glucose concentrations did not significantly differ during CON and IE. During CON: 1. PG change at the end of exercise was greater than during IE (P = .034); 2. all sensors overestimated PG more than during IE, as shown by SB (P < .001) and MARD (P < .001) comparisons. Classifying the performance according to the CEG, significant differences were found between the 2 sessions in distribution of points in A and B zones. CONCLUSIONS: the exercise affects the accuracy of currently available CGMs, especially during CON, suggesting, in this circumstance, the need to maintain blood glucose in a "prudent" range, above that generally recommended. Further studies are needed to investigate additional types of activities.

Abnormal serum alanine aminotransferase levels are associated with impaired insulin sensitivity in young women with polycystic ovary syndrome.

BACKGROUND AND AIM: Non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS) are both associated with insulin resistance.We assessed whether NAFLD is associated with impaired insulin sensitivity in PCOS women independently of age and total adiposity. SUBJECTS AND METHODS: We enrolled 14 young PCOS women with NAFLD, 14 women with PCOS alone and 14 healthy controls, who were matched for age, body mass index, and total body fat (by bio-impedance analyzer). NAFLD was diagnosed by the surrogate measure of abnormal serum alanine aminotransferase (ALT) concentrations (defined as ALT>19 U/l) after excluding other secondary causes of liver disease (alcohol, virus, and medications). Insulin sensitivity was measured by euglycemic hyperinsulinemic clamp. RESULTS: Insulin sensitivity was markedly decreased (p<0.001) in PCOS women with abnormal ALT levels, whereas it was similar between PCOS women with normal ALT levels andmatched healthy controls (8.3+/-2.5 vs 12.1+/-1.7 vs 13.2+/-1.8 mg/min x kg of fat-free mass, respectively). PCOS women with abnormal ALT levels also had higher plasma triglycerides and lower HDLcholesterol concentrations than those with PCOS alone. There was a strong inverse association between serum ALT levels and insulin sensitivity in the whole group of PCOS women (r=-0.59, p=0.0013). CONCLUSIONS: Abnormal serum ALT levels, as surrogate measure of NAFLD, are closely associated with impaired insulin sensitivity in young PCOS women in a manner that is independent from the contribution of age and total adiposity. Early recognition of NAFLD by radiological imaging tests in this group of young patients is warranted.

Detection of mutations in insulin receptor gene by denaturing gradient gel electrophoresis.

Denaturing gradient gel electrophoresis (DGGE) has been used to screen for mutations in the insulin receptor gene. Each of the 22 exons was amplified by the polymerase chain reaction (PCR). For each exon, one of the two PCR primers contained a guanine-cytosine (GC) clamp at its 5' end. The DNA was analyzed by electrophoresis through a polyacrylamide gel containing a gradient of denaturants. Two geometries for the gels were compared; the gradient of denaturants was oriented either parallel or perpendicular to the electric field. The sensitivity of the technique was evaluated by determining whether DGGE succeeded in detecting known mutations and polymorphisms in the insulin receptor gene. With parallel gels, 12 of 16 sequence variants were detected. The use of perpendicular gels increased the sensitivity of detection so that all 16 sequence variants were successfully detected when DNA was analyzed by a combination of perpendicular and parallel gels. Furthermore, DGGE was used to investigate a patient with leprechaunism whose insulin receptor genes had not previously been studied. Two mutant alleles were identified in this patient. The allele inherited from the father had a mutation substituting alanine for Val-28; in the allele inherited from the mother, arginine was substituted for Gly-366.

Insulin sensitivity, binding, and kinetics in pancreatogenic and type I diabetes.

Pancreatogenic diabetes (PD), secondary either to chronic calcific pancreatitis or to pancreatectomy, is characterized by higher frequency of hypoglycemic events during insulin therapy in comparison with type I insulin-dependent diabetes (IDD). Not only glucagon deficiency, but an enhanced peripheral tissue sensitivity to insulin could account for this metabolic behavior. We investigated several facets of insulin action, e.g., tissue sensitivity to insulin, insulin binding to red cells, and insulin kinetics in seven patients with PD in comparison with type I. Tissue sensitivity to insulin was evaluated by means of the glucose-insulin clamp technique as M/I x 100 ratio (mg . kg .-1 min-1/muU . ml-1), where M is the amount of glucose infused by Biostator GCIIS to clamp BG at basal level and I is the free insulin plateau concentration achieved by a primed-constant insulin infusion. At high BG 15 h after the last injection of regular insulin M/I x 100 was 7.79 (range 4.25-9.75) in PD and 4.20 (range 1.20-6.91) in D (P less than 0.05). At low and equal BG M/I x 100 was 8.55 (range 6.35-9.72) in PD and 3.42 (range 1.19-6.75) in D (P less than 0.01). The rate of endogenous glucose production was nearly totally suppressed in both groups of patients. Just before the two clamps, 125I-insulin specific binding to red cells was studied. The maximum specific binding was significantly higher in PD than in D at high BG (10.7 +/- 1.7 vs. 7.4 +/- 0.8/10(9) red cells) and at low and equal BG (12.4 +/- 1.2 vs. 6.8 +/- 0.8). Receptor concentration also was significantly higher in PD thant in D (P less than 0.02) while no significant differences were found in high affinity (Ke). Insulin kinetic data were analysed by using both "Model independent" (or noncompartmental) method and compartmental modeling. Patients with PD had significantly higher (P less than 0.05) plasma clearance of insulin.

Fasting plasma glucose variability predicts 10-year survival of type 2 diabetic patients: the Verona Diabetes Study.

OBJECTIVE: In the present study, we evaluated whether the coefficient of variation (CV) of fasting plasma glucose (FPG) over a 3-year period was a significant predictor of mortality in type 2 diabetic patients aged 56-74 years. RESEARCH DESIGN AND METHODS: All type 2 diabetic patients (n = 1,409) aged 56-74 years attending the Verona Diabetes Clinic and having at least two FPG determinations in each of the years 1984-1986 were followed for 10 years (1987-1996) to assess total and cause-specific mortality Patients were grouped into tertiles of mean and CV of FPG during 1984-1986. These parameters as well as sex, age, diabetes duration, insulin treatment, smoking, hypertension, and hypercholesterolemia were included in multivariate survival analyses. RESULTS: During the follow-up, 468 patients died. The CV of FPG was an independent predictor of total, cardiovascular, and cancer mortality. Mean FPG was a predictor of total mortality only when the CV of FPG was not included in the analyses. CONCLUSIONS: Long-term variability of fasting glucose is an independent predictor of mortality in patients with type 2 diabetes. The CV of FPG might be considered a useful additional parameter in the management of these patients.

Plasma concentrations of growth hormone during hyperglycemic clamp with or without somatostatin infusion in obese subjects.

It is known that obese subjects have a blunted GH secretory response to stimulation, but little is known about the inhibition of GH secretion in obesity. The present study was designed to evaluate the effects of obesity on the suppression of GH by hyperglycemia and/or somatostatin. Plasma GH concentrations were measured in eight nondiabetic obese subjects and eight nonobese healthy controls during a 4-h hyperglycemic clamp. During the third hour synthetic cyclic somatostatin-14 was infused at the rate of 2.5 nmol/min. Baseline plasma GH levels were similar in obese and nonobese subjects (0.9 +/- 0.1 vs. 0.8 +/- 0.2 micrograms/L; mean +/- SEM). In the last 20 min of the glucose infusion period preceding somatostatin administration (100-120 min of the study) plasma GH averaged 0.8 +/- 0.1 micrograms/L in obese patients and 0.4 +/- 0.1 micrograms/L in control subjects (P less than 0.01), with a reduction of 6 +/- 5% in the former and 35 +/- 10% in the latter (P less than 0.01). In both groups somatostatin infusion did not result in a further decrease in plasma GH. Discontinuation of the somatostatin infusion resulted in a rise in both groups; the increase was higher in nonobese subjects (8.1 +/- 3.8 vs. 2.3 +/- 0.9 micrograms/L in the period 220-240 min; P = NS). These results suggest that in human obesity, hyperglycemia has a diminished inhibitory effect on GH secretion, and somatostatin administration has no additional effect in either obese or nonobese nondiabetic subjects.

Insulin receptor on monocytes from patients with acromegaly and fasting hyperglycemia.

[125I]Insulin binding to insulin receptors on circulating monocytes was studied in 9 patients with acromegaly associated with fasting hyperglycemia and was compared to previously reported studies of 11 patients with acromegaly who had normal or nearly normal glucose tolerance and 29 normal volunteers. In the hyperglycemic acromegalic, as had been found in the normoglycemic acromegalic, the total receptor concentration per cell was decreased in proportion to the hyperinsulinemia, i.e. the receptor concentration was inversely related to the basal level of insulin, similar to what is found in patients with obesity, diabetes, and insulin-secreting tumors. However, the acromegalic patients with hyperglycemia failed to show the increase in affinity of the empty receptor that had previously been found in their normoglycemic counterparts. The failure to increase receptor affinity causes the cells of the hyperglycemic acromegalic patients to bind less insulin at each insulin concentration than do the cells of normoglycemic patients. Again, the abnormalities in the patients correlates very closely with abnormalities at the level of the insulin receptor, though the sequence of the molecular events that produce these changes remains to be determined.