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Acromegaly is a rare endocrine disease caused by hypersecretion of growth hormone, most commonly arising due to a pituitary adenoma. Diabetes mellitus is a common complication of acromegaly, occurring in approximately one-third of patients. The risk of diabetes mellitus in acromegaly is driven by increased exposure to growth hormone, which directly attenuates insulin signalling and stimulates lipolysis, leading to decreased glucose uptake in peripheral tissues. Acromegaly is a unique human model, where insulin resistance occurs independently of obesity and is paradoxically associated with a lean phenotype and reduced body adipose tissue mass. Diabetes mellitus in patients with acromegaly is associated with an increased risk of cardiovascular morbidity and mortality. Therefore, preventive measures and optimized treatment of diabetes mellitus are essential in these patients. However, specific recommendations for the management of diabetes mellitus secondary to acromegaly are lacking due to limited research on this subject. This Review explores the underlying mechanisms for diabetes mellitus in acromegaly and its effect on morbidity and mortality. We also discuss treatment modalities for diabetes mellitus that are suited for patients with acromegaly. Improved understanding of these issues will lead to better management of acromegaly and its associated metabolic complications., (© 2024. Springer Nature Limited.)

Introduction: Pasireotide, a somatostatin receptor ligand, is approved for treating acromegaly and Cushing's disease (CD). Hyperglycemia during treatment can occur because of the drug's mechanism of action, although treatment discontinuation is rarely required. The prospective, randomized, Phase IV SOM230B2219 (NCT02060383) trial was designed to assess optimal management of pasireotide-associated hyperglycemia. Here, we investigated predictive factors for requiring antihyperglycemic medication during pasireotide treatment., Methods: Participants with acromegaly or CD initiated long-acting pasireotide 40 mg/28 days intramuscularly (acromegaly) or pasireotide 600 μg subcutaneously twice daily during pre-randomization (≤16 weeks). Those who did not need antihyperglycemic medication, were managed with metformin, or received insulin from baseline entered an observational arm ending at 16 weeks. Those who required additional/alternative antihyperglycemic medication to metformin were randomized to incretin-based therapy or insulin for an additional 16 weeks. Logistic-regression analyses evaluated quantitative and qualitative factors for requiring antihyperglycemic medication during pre-randomization., Results: Of 190 participants with acromegaly and 59 with CD, 88 and 15, respectively, did not need antihyperglycemic medication; most were aged <40 years (acromegaly 62.5%, CD 86.7%), with baseline glycated hemoglobin (HbA 1c ) <6.5% (<48 mmol/mol; acromegaly 98.9%, CD 100%) and fasting plasma glucose (FPG) <100 mg/dL (<5.6 mmol/L; acromegaly 76.1%, CD 100%). By logistic regression, increasing baseline HbA 1c (odds ratio [OR] 3.6; P =0.0162) and FPG (OR 1.0; P =0.0472) and history of diabetes/pre-diabetes (OR 3.0; P =0.0221) predicted receipt of antihyperglycemic medication in acromegaly participants; increasing baseline HbA 1c (OR 12.6; P =0.0276) was also predictive in CD participants. Investigator-reported hyperglycemia-related adverse events were recorded in 47.9% and 54.2% of acromegaly and CD participants, respectively, mainly those with diabetes/pre-diabetes., Conclusion: Increasing age, HbA 1c , and FPG and pre-diabetes/diabetes were associated with increased likelihood of requiring antihyperglycemic medication during pasireotide treatment. These risk factors may be used to identify those who need more vigilant monitoring to optimize outcomes during pasireotide treatment., Competing Interests: UF-R reports travel grants and speaker honoraria from Ipsen, Recordati, and Novo Nordisk and advisory board fees from Novartis, Recordati, Novo Nordisk, and Xeris Pharmaceuticals Strongbridge. UF-R’s research salary was sponsored by a grant from Kirsten and Freddy Johansen’s Fund. MB reports receiving travel grants and speaker fees from Amryt, Recordati, Pfizer, Novartis, Ipsen, IBSA, Teva, and Berlin Chemie. PW reports receiving travel grants and speaker fees from Novartis, Ipsen, Recordati, Novo Nordisk, Xeris Pharmaceuticals (Strongbridge), and Lilly. PK reports participation in advisory board meetings by Novo Nordisk, Novartis, and Eli Lilly. AP is an employee of Recordati. AMP was an employee of Recordati when the analyses were conducted. SS has provided consultancy for Novartis and Chiasma. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2024 Feldt-Rasmussen, Bolanowski, Zhang, Yu, Witek, Kalra, Kietsiriroje, Piacentini, Pedroncelli and Samson.)

Cushing's syndrome, acromegaly and neuroendocrine disorders are characterized by an excess of counterregulatory hormones, able to induce insulin resistance and glucose metabolism disorders at variable degrees and requiring immediate treatment, until patients are ready to undergo surgery. This review focuses on the management of diabetes mellitus in endocrine disorders related to an excess of counterregulatory hormones. Currently, the landscape of approved agents for treatment of diabetes is dynamic and is mainly patient-centred and not glycaemia-centred. In addition, personalized medicine is more and more required to provide a precise approach to the patient's disease. For this reason, we aimed to define a practical therapeutic algorithm for management of diabetes mellitus in patients with glucagonoma, pheochromocytoma, Cushing's syndrome and acromegaly, based on our practical experience and on the physiopathology of the specific endocrine disease taken into account. This document is addressed to all specialists who approach patients with diabetes mellitus secondary to endocrine disorders characterized by an excess of counterregulatory hormones, in order to take better care of these patients. Care and control of diabetes mellitus should be one of the primary goals in patients with an excess of counterregulatory hormones requiring immediate and aggressive treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Guarnotta, Emanuele, Salzillo, Bonsangue, Amato, Mineo and Giordano.)

Purpose: The discrepancy between the biomarkers of disease's activity in acromegalic patients (GH and IGF-1) is almost frequent representing a challenge for the development of comorbidities in the long term. The aim of this study was to evaluate the prevalence and severity of metabolic comorbidities (diabetes, hypertension, and dyslipidemia) in surgically treated acromegalic patients with disease control and discordant GH and/or IGF-1 levels compared with those with concordant values., Patients and Methods: Retrospective monocentric observational study on acromegalic surgically treated patients with biochemical remission (group A) or mild discordant GH or IGF-1 levels (group B). Metabolic complications and medical therapy were assessed at diagnosis and at the last follow-up visit. Severity of the disease was set for drug titration or shift to another molecule or more than before., Results: There were 18 patients that met the inclusion criteria [group A: nine patients; group B: nine patients, follow-up 7 years (IQR 5.0;11.25)]. The prevalence of female patients was significantly higher in the remission group compared with the discordant group (p < 0.02). Considering metabolic complications, at the last follow-up, 61.1% was affected by hypertension, 33.3% by diabetes, and 61.1% by dyslipidemia, without differences between groups. Drug characteristics (dose, shift, number) during the follow-up did not differ significantly between groups., Conclusion: Metabolic complications, mainly dyslipidemia, are frequent in cured acromegalic patients, but GH/IGF-1 discrepancy does not seem to represent a risk factor for their presence or persistence. More extended studies are needed to confirm our results in a long-term period., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Romanisio, Pitino, Ferrero, Pizzolitto, Costelli, Antoniotti, Marzullo, Aimaretti, Prodam and Caputo.)

Objective: To compare the incidence of cancer in patients with acromegaly with that of the local population in China and explore possible risk factors., Methods: Data from 117 patients diagnosed with acromegaly at 2 centers between 2011 and 2022 were analyzed, and their cancer diagnoses were recorded. The cancer standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated by comparison with those of the local population. The patients were divided into 2 groups, having cancer diagnosis or not. The relationships between cancer and sex, body mass index, age, growth hormone levels, diagnosis delay, tumor size, disease duration, treatment, disease status, and other comorbidities were analyzed., Results: Eight (6.8%) of 117 patients were diagnosed with cancer. The incidence of overall (SIR = 3.29, 95% CI = 1.42-6.94), colorectal (SIR = 16.67, 95% CI = 4.45-42.67), and thyroid cancers (SIR = 14.29, 95% CI = 1.73-51.60) was increased, but that of lung cancer (SIR = 4.17, 95% CI = 0.50-15.05) was not. Diagnostic delay (10.1[8.6-14.3] vs 3.8[1.3-9.0]; P = .005) and duration of acromegaly (12.8[8.9-16.4] vs 5.6[2.3-10.9]; P = .008) were prolonged in the cancer group. Diabetes mellitus (odds ratio = 7.01, 95% CI = 1.23-39.99) was an independent risk factor for acromegaly with cancer., Conclusion: Acromegaly patients are at a higher risk of cancer and its association with diabetes mellitus. Considering the rarity of the disease, an Acromegaly Cancer Registry Center should be established in China as soon as possible., Competing Interests: Disclosure The authors have no multiplicity of interest to disclose., (Copyright © 2023. Published by Elsevier Inc.)

Objective: The results of previous studies on sex differences in mortality and comorbidities among patients with acromegaly are diverse. We assessed sex differences in mortality and the risk of complications in patients with acromegaly., Methods: We included 1884 patients with acromegaly with 1:50 age- and sex-matched 94 200 controls using the Korean nationwide claims database from 2009 to 2019., Results: During the median 5.51 years of follow-up, the acromegaly group had higher all-cause mortality than the control group (hazard ratio [HR] 1.74, 95% confidence interval [CI] 1.38-2.19), with higher risk in women than men (HR 2.17 vs 1.36). The most common cause of death was malignancy. Women with acromegaly aged ≥50 years exhibited significantly higher mortality than men with acromegaly aged ≥50 years (HR 1.74 vs 0.96). In a treatment subgroup other than surgery alone, women had a higher risk of mortality than men (HR 2.82 vs 1.58). Sex differences in mortality among patients with acromegaly remained equal after adjustment for the Charlson Comorbidity Index (CCI), socioeconomic status (SES), body mass index (BMI), alcohol consumption, smoking, fasting plasma glucose, creatinine, and total cholesterol. Patients with acromegaly had elevated risks of developing major adverse cardiovascular events (MACE), atrial fibrillation, obstructive sleep apnea (OSA), diabetes mellitus (DM), end-stage renal disease (ESRD), Parkinson's disease (PD), depression, and malignancy than age- and sex-matched controls, with a higher risk of OSA and DM in women than men., Conclusions: The risk of mortality and complications in patients with acromegaly compared to age- and sex-matched controls was higher in women than in men., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Acromegaly (AC) and Cushing's disease (CD) increase morbidity and mortality due to cardio-metabolic alterations, and overall cause frailty in the affected patients, potentially making them more susceptible to infective diseases. However, up to now, very few studies evaluated the course of COVID-19 disease in this setting., Methods: We investigated epidemiology, course, and outcomes of COVID-19 disease in patients with AC or CD, managed in the Endocrine Unit of a Sicilian University Hospital during 2 years of pandemic outbreak., Results: We enrolled 136 patients with AC or CD (74 and 62 cases, respectively, 39 males) from Sicily and Calabria regions. Incidence of Sars-CoV-2 infection in these subjects was lower than in the general population, becoming quite similar after vaccines introduction (11%). No difference was observed concerning prevalence. Mean age of infected patients (IPs) was significantly lower than the unaffected ones (p < 0.02). No differences were found for sex, BMI, disease control, occurrence of diabetes mellitus, OSAS, cardiomyopathy, and hypopituitarism. The rate of IPs was similar in AC and CD patients' groups. None of them died., Conclusions: In conclusion, we did not find a significantly different incidence of Sars-CoV-2 infection in AC or CD patients compared to the general population. IPs were younger than the unaffected patients, but sex, BMI, or diabetes mellitus were not risk factors for infection/worse outcomes. Nevertheless, these results could have been biased by a safer behavior probably adopted by older and more complicated patients., (© 2023. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Secondary diabetes mellitus (DM) is a common complication of acromegaly, encountered in up to 55% of cases. Vice versa, the prevalence of acromegaly is markedly higher in cohorts of patients with type 2 DM (T2DM). The presence of secondary DM depends primarily on acromegaly status and is associated with increased cardiovascular morbidity, malignancy rate and overall mortality. The principal pathophysiologic mechanism is increased insulin resistance due to excessive lipolysis and altered fat distribution, reflected at the presence of intermuscular fat and attenuated, dysfunctional adipose tissue. Insulin resistance is ascribed to the direct, diabetogenic effects of growth hormone (GH), which prevail over the insulin-sensitizing effects of insulin-like growth factor 1 (IGF-1), probably due to higher glucometabolic potency of GH, IGF-1 resistance, or both. Inversely, GH and IGF-1 act synergistically in increasing insulin secretion. Hyperinsulinemia in portal vein leads to enhanced responsiveness of liver GH receptors and IGF-1 production, pointing towards a mutually amplifying loop between GH-IGF-1 axis and insulin. Secondary DM occurs upon beta cell exhaustion, principally due to gluco-lipo-toxicity. Somatostatin analogues inhibit insulin secretion; especially pasireotide (PASI) impairs glycaemic profile in up to 75% of cases, establishing a separate pathophysiologic entity, PASI-induced DM. In contrast, pegvisomant and dopamine agonizts improve insulin sensitivity. In turn, metformin, pioglitazone and sodium-glucose transporters 2 inhibitors might be disease-modifying by counteracting hyperinsulinemia or acting pleiotropically. Large, prospective cohort studies are needed to validate the above notions and define optimal DM management in acromegaly., (© 2023. The Author(s).)

Background and Objectives: Acromegaly is a rare disease associated with increased levels of growth hormones (GHs) that stimulates the hepatic production of insulin growth factor-1 (IGF-1). Increased secretion of both GH and IGF-1 activates pathways, such as Janus kinase 2/signal transducer and activator of transcription 5 (JAK2/STAT5), and mitogen-activated protein kinase (MAPK), involved in the development of tumors. Materials and Methods: Given the disputed nature of the topic, we decided to study the prevalence of benign and malignant tumors in our cohort of acromegalic patients. In addition, we aimed to identify risk factors or laboratory parameters associated with the occurrence of tumors in these patients. Results: The study group included 34 patients (9 men (25.7%) and 25 women (74.3%)). No clear relationship between the levels of IGF-1 or GH and tumor development could be demonstrated, but certain risk factors, such as diabetes mellitus (DM) and obesity, were more frequent in patients with tumors. In total, 34 benign tumoral proliferations were identified, the most common being multinodular goiter. Malignant tumors were present only in women (14.70%) and the most frequent type was thyroid carcinoma. Conclusions: DM and obesity might be associated with tumoral proliferation in patients with acromegaly, and findings also present in the general population. In our study we did not find a direct link between acromegaly and tumoral proliferations.

Diabetes mellitus (DM) has a heterogenous cause, and the exact pathogenesis differs between patients. Most diabetic cats have a cause similar to human type 2 DM but, in some, DM is associated with underlying conditions, such as hypersomatotropism, hyperadrenocorticism, or administration of diabetogenic drugs. Predisposing factors for feline DM include obesity, reduced physical activity, male sex, and increasing age. Gluco(lipo)toxicity and genetic predisposition also likely play roles in pathogenesis. Prediabetes cannot be accurately diagnosed in cats at the current time. Diabetic cats can enter remission, but relapses are common, as these cats might have ongoing, abnormal glucose homeostasis., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Acromegaly is often complicated by impaired glucose tolerance. The accuracy of glycated hemoglobin (HbA 1c ) and glycated albumin (GA) levels in representing glycemic profiles in patients with endocrine disorders, such as acromegaly, is unclear. This retrospective study reviewed data from patients whose GA levels had been recorded. 14 patients with acromegaly without diabetes mellitus (DM) (the acromegaly group), 15 patients with severe adult GH deficiency without DM (the growth hormone deficiency (GHD) group), and 55 nondiabetic patients (the control group) were included in this study. GA levels were significantly increased in the acromegaly group compared with the control and GHD groups, but no significant differences were observed between the control and GHD groups. The three groups were matched using propensity score matching (13 patients with acromegaly, 13 with GHD, and 13 control patients). Nonetheless, the results after matching were the same as those before matching. GA levels in the acromegaly group were significantly associated with plasma glucose (PG) levels at 0, 30, and 120 min after a 75-g oral glucose tolerance test (OGTT). Further, GH levels at 120 min after a 75-g OGTT in the acromegaly group were significantly correlated with GA levels and the difference in PG levels at baseline and 30 min. Our findings suggest that increases in PG levels attributable to excess GH after glucose loading are related to increases in GA levels in patients with acromegaly without DM. Hence, both HbA 1c and GA should be checked to accurately assess impaired glucose tolerance in patients with acromegaly.

Purpose: Acromegaly is a rare disease due to growth hormone (GH)-secreting pituitary adenoma. GH and IGF-1 levels are usually congruent, indicating either remission or active disease; however, a discrepancy between GH and IGF-1 may occur. We aimed to evaluate the outcome of diabetes mellitus (DM) and hypertension (HT) in acromegalic patients with congruent GH and/or IGF-1 levels vs. discordant biochemical parameters., Methods: Retrospective analysis of the data of 3173 patients from the Liege Acromegaly Survey (LAS) allowed us to include 190 patients from 8 tertiary referral centers across Europe, treated by surgery, with available data concerning DM and HT both at diagnosis and at the last follow-up (LFU). We recorded the number of anti-HT and anti-DM drugs used at the first evaluation and at LFU for every patient., Results: Ninety-nine patients belonged to the REM group (concordant parameters), 65 patients were considered as GH dis (high random GH/controlled IGF-1), and 26 patients were considered as IGF-1 dis (high IGF-1/controlled random GH). At diagnosis, 72 patients (37.8%) had HT and 54 patients had DM (28.4%). There was no statistically significant difference in terms of the number of anti-HT and anti-DM drugs at diagnosis versus LFU (mean duration: 7.3 ± 4.5 years) between all three groups., Conclusion: The long-term outcome of DM and HT in acromegaly does not tend to be more severe in patients with biochemical discordance in comparison with patients considered as in remission on the basis of concordant biological parameters, suggesting that patients with biochemical discordance do not require a closer follow-up.

Introduction: Acromegaly is a rare disease due to oversecretion of growth hormone (GH). Even though the disease is often portrayed by its most apparent clinical features, given the abundance of GH receptors throughout the body, it truly is a systemic disease leading to numerous complications and comorbidities. A distinct medical issue in the context of acromegaly is diabetes: It can be a complication as a consequence of GH excess and its mediators, but it can also result from treatment of acromegaly., Areas Covered: This review provides an overview of the effects of acromegaly pathophysiology on glucose homeostasis. Furthermore, it devotes an extensive section on the influence that acromegaly treatment has on glucose metabolism, including approved as well as currently investigated drugs. It also summarizes observations from the use of anti-diabetic medication in patients with acromegaly., Expert Opinion: Glucose imbalance is an important aspect of acromegaly comorbidity and deserves more attention. Even though numerous studies have investigated glucose homeostasis in acromegaly, there is still a clear need for more basic, translational, and also clinical research to advance the understanding of the underlying mechanisms and how to best address them.

Acromegaly is a disease characterized by overproduction of growth hormone (GH). As a consequence of excessive GH secretion, circulating insulin-like growth factor-I (IGF-I) is elevated in active (untreated) acromegaly. IGF-I is often used as a marker of disease activity and growth hormone status in acromegaly. Although IGF-I can directly improve insulin sensitivity and glucose uptake in muscles, the excessive GH secretion in active acromegaly frequently leads to insulin resistance, glucose intolerance and even diabetes. In this review evidence will be discussed that in active acromegaly chronically elevated IGF-I, insulin and soluble Klotho (S-Klotho) levels play a pathophysiological role in the development of IGF-I receptor (IGF-IR) resistance. It is postulated that as soon as circulating IGF-I, insulin and S-Klotho rise above a certain level the IGF-IR becomes relatively resistant to actions of IGF-I. The development of a degree of IGF-IR resistance for metabolic actions may help to explain why in active acromegaly diabetogenic effects of GH predominate and are not completely counteracted and neutralized by elevated circulating levels of IGF-I. Further studies are necessary in order to support this hypothesis., (Copyright © 2020 The Author. Published by Elsevier Ltd.. All rights reserved.)

A 12-year-old, castrated male cat with diabetes mellitus was diagnosed with acromegaly and examined with magnetic resonance imaging (enlarged pituitary gland, 8 mm); serum hormone concentrations were measured. After the first course of radiation therapy (4 Gy, 12 fractions), insulin administration was not required from day 420 after diagnosis. Enlarged pituitary tumor (8 mm) recurred, and insulin dosage amount of the cat was increased on day 1,065. The second course of radiation therapy (6 Gy, 4 fractions) was performed on day 1,201 and insulin administration was again discontinued. However, the cat died from lymphoma on day 1,397. Postmortem examination revealed pituitary adenoma. Most tumor cells were positive for chromogranin A, synaptophysin, and growth hormone immunohistochemistry. The pancreatic islet cells revealed diffuse hyperplasia. We achieved long-term successful management of an acromegalic cat with two courses of RT. However, a protocol for a second course of RT for feline recurrent pituitary tumor should be further discussed.

Diabetes is recognized as one of the most common acromegaly co-morbidities with a prevalence ranging 20-53%, while over one-third of these patients have an altered lipid profile. In fact, as in the non-acromegalic population, carbohydrate and lipid metabolism abnormalities are closely linked. Long term exposure to an excess of growth hormone (GH) and Insulin-like growth factor-1 concentrations results in insulin resistance and an increased hepatic glucose production. The lipolytic effect of GH results in the mobilization of free fatty acids that further contributes to the decreased insulin sensitivity found in these patients. Some studies suggest that the presence of diabetes contributes to the increased mortality of acromegaly, although this remains controversial. Successful treatment of acromegaly usually results in significant, albeit incomplete improvements of the abnormal metabolic profile., (© 2018 S. Karger AG, Basel.)

Purpose of Review: Acromegaly is a clinical syndrome which results from growth hormone excess. Uncontrolled acromegaly is associated with cardiovascular mortality, due to an excess of risk factors including diabetes mellitus, hypertension and cardiomegaly. Diabetes mellitus is a frequent complication of acromegaly with a prevalence of 12-37%. This review will provide an overview of a number of aspects of diabetes mellitus and glucose intolerance in acromegaly including the following: 1. Epidemiology and pathophysiology of abnormalities of glucose homeostasis 2. The impact of different management options for acromegaly on glucose homeostasis 3. The management options for diabetes mellitus in patients with acromegaly RECENT FINDINGS: Growth hormone and IGF-1 have complex effects on glucose metabolism. Insulin resistance, hyperinsulinaemia and increased gluconeogenesis combine to produce a metabolic milieu which leads to the development of diabetes in acromegaly. Treatment of acromegaly should ameliorate abnormalities of glucose metabolism, due to reversal of insulin resistance and a reduction in gluconeogenesis. Recent advances in medical therapy of acromegaly have varying impacts on glucose homeostasis. These adverse effects influence management choices in patients with acromegaly who also have diabetes mellitus or glucose intolerance. The underlying mechanisms of disorders of glucose metabolism in patients with acromegaly are complex. The aim of treatment of acromegaly is normalisation of GH/IGF-1 with reduction of co-morbidities. The choice of therapy for acromegaly should consider the impact of therapy on several factors including glucose metabolism.

Background: N-terminal type III procollagen propeptide (PIIINP) is a biomarker of soft tissue proliferation. Hypersomatotropism (HS) is associated with soft tissue proliferation., Hypothesis: Serum PIIINP is increased in cats with HS and decreases with effective treatment, and may be an additional tool in the diagnosis and treatment of feline HS., Animals: Cats with uncomplicated diabetes mellitus (DM; n = 30) and with HS-induced DM (HSDM; n = 30). Pre- and posttreatment samples were available from 5 cats undergoing radiotherapy (RT) and 16 cats undergoing hypophysectomy (HPX)., Methods: Retrospective and prospective cross-sectional study. Analytical performance of a serum PIIINP ELISA was assessed and validated for use in cats. PIIINP and insulin-like growth factor 1 (IGF-1) radioimmunoassays (RIA) were performed pre- and post-treatment in cats with DM and HSDM. PIIINP and IGF-1 were compared between cats treated by RT and HPX., Results: Serum PIIINP concentrations were significantly higher (P < .001) in HSDM cats (median, 19.6 ng/mL; range, 1.7-27.9) compared to DM cats (median, 5.0 ng/mL; range, 2.1-10.4). A cut-off of 10.5 ng/mL allowed differentiation between DM and HSDM cats with 87% sensitivity and 100% specificity (area under the curve [AUC], 0.91; 95% confidence interval [CI], 0.82-1). After RT, PIIINP increased significantly (P = .043) with no significant change in IGF-1 concentrations. After HPX, serum PIIINP (P = .034) and IGF-1 concentrations (P < .001) decreased significantly., Conclusion and Clinical Importance: PIIINP concentrations are increased in cats with untreated HSDM compared to those with DM, demonstrating the effect of excess GH on soft tissue. PIIINP concentrations decreased after HPX in most HSDM cats., (Copyright © 2016 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: The risk and mortality due to cancer in patients with acromegaly have been previously investigated. Although GH/IGF-1 excess provides a probable pathophysiological explanation, the degree of IGF-1 excess and the role in acromegaly-associated neoplasms of diabetes, a common comorbidity in acromegaly with known association with cancer, remains unclear., Methods: Acromegalic patients treated in three Canadian referral centers (Toronto, Montreal, Edmonton) were included. All available clinical information was recorded including: age, initial and last percentage of the upper limit of normal (%ULN) IGF-1 levels, comorbidities and other neoplasms (benign and malignant)., Results: 408 cases were assessed. 185 were women (45.3%), 126 (30.9%) developed extra-pituitary neoplasms: 55 malignant and 71 benign. The most frequent anatomic site was the gastrointestinal tract (46 [11.3%]), followed by head and neck (36 [8.8%]) and multiple locations (14 [3.4%]). 106 (26.0%) cases had diabetes. Initial IGF-1 was significantly higher in men older than 50 (380.15 vs. 284.78, p = 0.001) when compared to men younger than 50. Diabetics showed significantly higher initial IGF-1 (389.38 vs. 285.27, p = 0.009), as did diabetics older than 50 compared with those without diabetes. 45.3% (48/106) of cases with diabetes developed extra-pituitary neoplasms vs. 24.3% (71/292) without diabetes (p = 0.001, OR: 2.576 95%CI 1.615-4.108). 22.6% (24/106) of cases with diabetes developed malignant tumors vs. 9.2% (27/292), (p < 0.001, OR 2.873, 95%CI 1.572-5.250)., Conclusions: These data suggest that acromegalic patients with diabetes are more likely to develop extra-pituitary neoplasms and their initial IGF-1 levels are higher. The contribution of IGF-1 vs. diabetes alone or in combination in the development of extra-pituitary neoplasms warrants further investigation.

The purpose of this study was to evaluate the safety of the oral glucose tolerance test (OGTT) and its capacity to suppress growth hormone (GH) in diabetic patients without acromegaly. A total of 135 diabetic patients submitted to the OGTT for GH suppression were studied. The following selection criteria were applied: age between 20 and 70 years; body mass index≥18.5 and ≤27 kg/m2; absence of kidney, liver, or thyroid disease; no use of estrogens, androgens, corticosteroids, or levothyroxine. Adequate suppression of GH was defined as a nadir below the cut-off established for a sample of 200 normoglycemic subjects (<0.25 µg/L for men, <0.74 µg/L for premenopausal women, and <0.5 µg/L for postmenopausal women). Acromegaly was diagnosed in five patients. Among the 130 diabetic patients without known pituitary disease or a clinical suspicion of acromegaly, 95.5% of men, 94% of premenopausal women, and 96.6% of postmenopausal women presented adequate GH suppression (vs 97.5% of normoglycemic controls). In all patients without acromegaly, the lowest GH levels (nadir) were achieved after the administration of glucose and not during baseline measurement. None of the patients had acute complications [ketoacidosis, hyperosmolar state, and symptomatic marked hyperglycemia (>300 mg/dL)] on the day of the test and up to 3 days thereafter. We demonstrated the safety of the OGTT and its capacity to suppress GH in diabetic patients without acromegaly. In addition, we suggest the adoption of a protocol to prevent possible risks of the OGTT in patients with diabetes.

Acromegaly is frequently associated with alterations of glucose metabolism but factors predisposing these patients to exhibit impaired glucose tolerance or overt diabetes at diagnosis are poorly understood. This study included 148 patients with newly diagnosed acromegaly (80 men; mean age: 45 ± 20 year). All patients underwent an oral glucose tolerance test (OGTT), unless already treated for diabetes. Insulin sensitivity (S) and β-cell function (B) were also evaluated by homeostasis model assessment (HOMA). Normal glucose tolerance (NGT) was observed in 67 patients (46 %), impaired fasting glycaemia (IFG) or glucose tolerance (IGT) were found in 39 (26 %), and diabetes mellitus (DM) in 42 (28 %). NGT patients were 10 years younger than patients with abnormal glucose metabolism (p < 0.001) and diabetic patients had a higher BMI (p < 0.05). While HOMA-S was similar, HOMA-B was reduced in the IFG/IGT group (p < 0.05) and further in the DM group (p < 0.001). IGF-I z-score was higher in IFG/IGT (5.2 ± 1.4) and DM patients (5.4 ± 1.3) than in NGT patients (4.4 ± 1.3; p < 0.05), but fasting and post-OGTT GH levels were not different between groups. In multivariate analyses, family history of diabetes and IGF-I were associated with hyperglycaemia, BMI and IGF-I predicted insulin resistance, and age was inversely correlated with β-cell function. Impaired glucose metabolism is present in more than 50 % of patients at diagnosis of acromegaly, and is associated with an older age, a higher BMI, a family history of diabetes and a higher IGF-I z-score, but not with fasting or post-OGTT GH levels.

This article summarizes the key features and clinical considerations related to preoperative management and planning for the care of patients of common endocrine disorders (diabetes mellitus, adrenal insufficiency, thyroid disease), a less common disorder but one that has significant perioperative implications (acromegaly), and 2 disorders for which preoperative management is essential to good postoperative outcomes (pheochromocytoma and carcinoid syndrome). There are few evidence-based guidelines for preoperative management of chronic endocrine disease; hence, this review is based on recent subspecialty society consensus guidelines and professional society clinical practice recommendations., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: Pituitary apoplexy is a rare clinical syndrome associated with rapid enlargement of a pituitary mass. We report the initial presentation, subsequent course and outcome of an acromegalic patient who developed spontaneous remission following pituitary apoplexy with pathologic findings of tumor infarction., Clinical Presentation: A 38 year-old man with typical acromegalic features was referred to our hospital. He had been diabetic and hypertensive. His basal GH and IGF-1 levels were high (80 µg/L and 747 ng/mL respectively). Sella MRI showed a macroadenoma about 19×20 mm in size. He admitted to emergency department with complains of severe frontal headache accompanied by nausea and vomiting two days after MRI was taken. His neurological examination and visual field test were normal. Emergent MRI of the sella disclosed an enhancing intrasellar mass of 24×23 mm compressing the optic chiasm. The patient underwent transsphenoidal decompression of the lesion. Histological examination revealed an adenomatous tissue showing nonhemorrhagic coagulation necrosis. Before surgery, his GH levels declined to 2.72 µg/L spontaneously and after surgery he was in remission even leading to a state of growth hormone deficiency., Conclusion: When apoplexy occurs in functioning adenomas, it may cause spontaneous remission. However pituitary apoplexy due to tumor infarction is very rare. Various precipitating factors have been reported in 25-30% of pituitary apoplexy patients. Diabetes mellitus and diabetic ketoacidosis are one of these. The presence of contrast media induced endothelial swelling with the result of hypoperfusion and diabetes mellitus associated vasculopathy might be a precipitating factor in this patient.

Background: Diabetes mellitus is frequently observed in patients with acromegaly. Current therapies for acromegaly may impact glucose regulation, influencing insulin sensitivity and secretion. The question whether these therapies modify control and progression of diabetes once present is still open., Aim: Aim of our study is to analyze glucose control in acromegalic patients with diabetes, evaluating the relation with treatments for GH excess and for diabetes., Methods: Seventy patients with acromegaly and diabetes were studied. Duration and treatments of acromegaly and diabetes were recorded, together with clinical and metabolic parameters., Results: Most patients (92.8%) were treated with somatostatin analogs (SSA), either alone or in combination with dopamine-agonists (20%) or pegvisomant (15.7%); 7.1% of patients had been treated by surgery alone. Metformin (65.7%), alone or in combination with other hypoglycemic drugs, was the most frequent treatment for diabetes, followed by insulin (21.5%). Only 15.7% were treated with diet alone. The whole cohort showed a very good control of diabetes and acromegaly. Median glycated hemoglobin was 6.4% (5.9-7). IGF-I was within normal range for age in most patients. No relation was observed between duration of acromegaly or diabetes and metabolic control. SSA had a negative effect on insulin secretion, but these effects did not influence glucose control. Finally, we observed a low prevalence of nephropathy (6%) and retinopathy (20%)., Conclusions: Our study shows that a good control of hyperglycemia can be obtained with success in the majority of acromegalic patients with diabetes, independently of the type of treatment for GH excess.

Objectives: To evaluate the presence of diabetes mellitus (DM) in a cohort of patients with acromegaly., Methods: This was a cross sectional study., Results: Fifty-eight acromegalic patients were assessed. Only 29% met the criteria for cure, and 27% had the disease controlled. Twenty-two had DM; HbA1c was equal to 7.34 ± 2.2%. Most of the diabetic patients (18 out of 22, 82%) did not meet criteria for cure. They were more often hypertensive [16/22 (73%) vs. 17/36 (46%), p = 0.04], and used statins more frequently [14/22 (64%) vs. 8/36 (21%), p = 0.004]. After regression analysis, hypertension was associated with diabetes [odds ratio (OR): 9.28 (95% CI: 1.59 - 54.00), p = 0.01], and cured/ controlled acromegaly was associated with protection against the presence of diabetes [OR: 0.17 (95% CI: 0.03 - 0.78), p = 0.02]., Conclusions: The presence of DM was associated with active acromegaly and presence of hypertension. However, absolute levels of GH and IGF-1 did not differ between patients with and without diabetes.

Insulin resistance is defined as decreased sensitivity to insulin. Insulin resistance is an important component of the pathogenesis of type 2 diabetes mellitus (DM), and resolution of peripheral insulin resistance in cats with type 2 DM together with good glycemic control may result in diabetic remission. In insulin-dependent diabetic cats, insulin resistance is manifested clinically as an inadequate response to an appropriate pharmacologic dose of insulin. This article focuses on the clinical problem of insulin resistance in insulin-dependent diabetic cats., (Copyright 2010 Elsevier Inc. All rights reserved.)

The secondary occurrence of type 2 diabetes with various hormonal diseases (e.g. pituitary, adrenal and/or thyroid diseases) is a recurrent observation. Indeed, impaired glucose tolerance (IGT) and overt diabetes mellitus are frequently associated with acromegaly and hypercortisolism (Cushing syndrome). The increased cardiovascular morbidity and mortality associated with acromegaly and Cushing syndrome may partly be a consequence of increased insulin resistance that normally accompanies hormone excess. Acromegalic patients are insulin resistant, both in the liver and in the periphery, displaying hyperinsulinemia and increased glucose turnover in the basal post-absorptive states. The prevalence of diabetes mellitus and that of IGT in acromegaly is reported to range 16-56%, whereas the degree of glucose tolerance seems correlated with circulating growth hormone (GH) levels, age, and disease duration. Moreover, a family history of diabetes and concomitant presence of arterial hypertension have been found to predispose to diabetes as well. GH has physiological effects on glucose metabolism, stimulating gluconeogenesis and lipolysis, which results in increased blood glucose and free fatty acid levels. Conversely, insulin-like growth factor 1 (IGF-I) enhances insulin sensitivity primarily on skeletal muscles. However, in acromegaly, increased IGF-I levels are unable to counteract the insulin-resistance status determined by GH excess. Therapy with somatostatin analogues (SSAs) induce control of GH and IGF-I excess in the majority of patients, but their inhibitory effect on pancreatic insulin secretion might complicate the overall effect of this treatment on glucose tolerance. Hypercortisolism produces visceral obesity, insulin resistance, and dyslipidemia that together with hypertension, hypercoagulability, and ventricular morphologic and functional abnormalities increase cardiovascular risk, and persist up to 5 years after resolution of hypercortisolism. Hypercortisolism leads to hyperglycaemia and reduced glucose tolerance, determines insulin resistance, stimulates hepatic gluconeogenesis and glicogenolisis. In Cushing syndrome the prevalence of diabetes varies between 20 and 50%, but probably this prevalence is underestimated, as not always an oral glucose tolerance test is performed in the presence of an apparently normal fasting glycaemia. Again, disease duration, rather than hormone levels, seems to be the major determinant in the occurrence of systemic complications in Cushing syndrome. Due to the impact they have on mortality and morbidity in both acromegaly and Cushing syndrome, these complications should be treated aggressively. In patients with neuroendocrine tumours (NETs) the occurrence of altered glucose tolerance may be due to a decreased insulin secretion, like it happens in patients who underwent pancreatic surgery and in those with pheochromocytoma, or to an altered counterbalance between hormones, such as in patients with glucagonoma and somatostatinoma. Moreover, SSAs represent a valid therapeutic choice in the symptomatic treatment of NETs, and also in this case the medical therapy of the primary disease, may have a significant impact on the prevalence of glucose metabolism imbalance. In thyroid disorders, an abnormal glucose tolerance may be principally encountered in hyperthyroidism. The pathogenesis is complex and scant data on prevalence and severity are found in the literature. Adequate treatment for glucose imbalance is mandatory in these peculiar patients in line with the American Diabetes Association and the European Association for the Study of Diabetes consensus statement. In particular, since traditional insulins have two features that may complicate therapy (absorption profiles, delayed onset of action and peak activity), the new insulin analogues could be of particular interest in the management of the secondary diabetes associated with endocrinopathies, considering the frailty of these patients. Indeed, it has been demonstrated that insulin glargine, given once daily, reduces the risk of hypoglycaemia compared with other formulations, and can facilitate a more aggressive insulin treatment in this class of patients.

A diabetic acromegalic man, not cured after surgery and radiosurgery, received lanreotide i.m. with great clinical and biochemical improvement. He required NPH insulin (76 to 84 units/day) to control his diabetes mellitus. Thirty-six hours after changing to LAR-octreotide (20 mg i.m/month) he presented symptomatic hypoglycemia, repeated at 48 and 72 h (50 mg/dL), despite reducing insulin to 26 Units/day. Thereafter, he reduced insulin by 30 to 50% for the first week after each LAR-octreotide injection, and gradually increased it again over the next 3 weeks. This situation persists after every injection 3 years later; this consistent behavior supports a specific effect of LAR-octreotide, and not a by chance phenomenon. No marked changes in circulating GH, IGF-1, immunoreative insulin, C-peptide, testosterone and glucose were observed prior to, and 3, 7, 14, 21, and 28 days after LAR-octreotide; however, there was 28% fall in plasma glucagon after 7 days, which rose thereafter. C-peptide (< 1.8 ng/mL) was indicative of decreased beta-cell function. To our knowledge, this is the first report of such a distinct differential behaviour of blood glucose and insulin requirements with different somatostatin analogs, and is worth recalling when starting an insulin-treated diabetic patient on this treatment. It may be related to a preferential binding of LAR-octreotide to subtype 2 somatostatin receptors in the pancreas, while lanreotide preferentially binds to subtype 5, not expressed in this tissue; this would explain the fall in glucagon, in parallel to the decrease in insulin requirements after LAR-octreotide; however, a contribution of differences in the effect of both somatostatin analogues on postreceptor signalling systems and/or intestinal carbohydrate absorption cannot be entirely ruled out.

The clinical findings and management of five cats with abnormalities consistent with acromegaly were examined retrospectively. Growth hormone (GH) concentrations were elevated in four cats. In one, a minimal elevation of GH was accompanied by a marked elevation in insulin-like growth factor-1 (IGF-1). Insulin-like growth factor-1 concentrations supported the diagnosis in three of four cats measured, but was not elevated initially in one cat, despite a markedly elevated GH concentration. These findings suggest that elevated IGF-1 concentrations are a reliable indicator of acromegaly, but that values within the reference range do not exclude such a diagnosis. Clinical signs of acromegaly were similar to those previously reported, although upper respiratory stridor occurred in one cat, and insulin-resistant diabetes mellitus was not a consistent feature. Despite the lack of a widely available definitive treatment for acromegaly, good control of the clinical signs of diabetes mellitus can be achieved for long periods despite high doses of insulin often being required., (Copyright 2000 European Society of Feline Medicine.)

In a retrospective study glucose metabolism was investigated in 206 patients with acromegaly and 131 patients with Cushing's disease. 40.5% of the patients with hypersomatotropism and 32.0% of the patients with hypercortisolism suffered from overt diabetes mellitus. Impaired glucose tolerance was present prior to therapy in 28.2% and 30.6% of the patients, respectively. In acromegaly the incidence of overt diabetes mellitus was higher in women than in men, but no difference existed in the distribution of impaired glucose tolerance between both sexes. No correlation was found between growth hormone levels and occurrence of diabetes. In acromegaly and Cushing's disease overt diabetes increased with advanced age. Diabetes mellitus occurred independently from the etiology of hypercortisolism.

Female pet dogs exhibiting either glucose intolerance alone or glucose intolerance and acromegaly were investigated. Some dogs developed the disorder(s) during dioestrus and some animals developed the disorder(s) after they were given medroxyprogesterone acetate (MPA). Elevated fasting plasma glucose levels (12.3 +/- 1.9 mM, mean +/- SEM) were accompanied by fasting hyperinsulinaemia (144 +/- 21 microU/ml, mean +/- SEM) and drastic elevation of plasma growth hormone (GH) levels (112.6 +/- 45 ng/ml, mean +/- SEM). An iv glucose tolerance test (IVGTT) performed on all dogs revealed non-suppressibility of GH levels and glucose intolerance. Plasma concentrations of glucose, insulin and GH during IVGTT in affected dogs differed significantly from the concentrations measured in normal dogs during the same test. MPA withdrawal and/or ovariohysterectomy (OVx-HYx) in affected animals was followed by reversal of GH levels to normal and improved glucose tolerance. Acromegaly associated soft tissue changes were also reversible after MPA withdrawal and/or OVx-HYx when GH levels had dropped. In 5 dogs which had developed diabetes during dioestrus and in which a spontaneous decrease in plasma progesterone occurred during the investigation a concomittant decrease in GH levels was observed. Plasma GH measured at different stages of pregnancy in 45 dogs was found to be elevated in one animal only. The results show that the development of spontaneous diabetes/acromegaly occurring in some female dogs is related to progestagen (progesterone/MPA) exposure and that reversal of the signs is achieved by progesterone/MPA withdrawal. The results suggest that diabetes/acromegaly in the dogs studied was caused by progesterone/MPA-evoked GH elevation. Finally, the findings also suggest that the GH axis normally not appreciably responsive to progestagen exposure in some dogs becomes and/or is paradoxically controlled by physiologic levels of endogenous progesterone or low doses of MPA.

A 42-year-old man with diabetes mellitus and probably acromegaly had a pituitary apoplexy with left-sided oculomotor palsy. There was an immediate fall in blood glucose concentration. Pituitary insufficiency promptly developed. Blood glucose levels remained normal for the next two years. During the first year after the pituitary apoplexy, severe proliferative retinopathy developed in the left eye, which became almost blind. Only mild retinopathy was present on the right side. Plasma concentrations of growth hormone remained low after the apoplexy, and the acromegalic features subsided. The explanation of these findings may be that the proliferative retinal angiopathy was caused by compression of the cavernous sinus at the time of the apoplexy. This would lead to impaired venous drainage, thus resembling occlusion of the central retinal vein, which may cause retinopathy similar to that seen in diabetes mellitus.

Glucagon is secreted not only by A2-cells of the pancreatic islets but also by A cells in the gastric fundus and duodenum. Several reports have demonstrated that the glucagon plasma concentration is increased in genetic diabetes as well as in many conditions associated with a decreased glucose tolerance such as hepatic cirrhosis, myocardial infarction, infectious diseases, burns, taumatic shock, glucagonomas, acute pancreatitis, acromegaly, pheochromacytoma and Cushing's syndrome. Hyperglucagonemia is particularly important in diabetic ketoacidosis and in non-ketotic hyperosmolar coma. The mechanisms responsible for the diabetic's hyperglucagonemia remain controversial. According to several authors, the increased glucagon secretion is, for its main part, secondary to a prolonged defect in insulin secretion and thus relatively insensitive to an acute insulin administration. According to others, the A cell abnormality is of primary origin, independant from insulin deficiency and its effects are cumulative with those of the insulin lack. Several reports dealing with induced or spontaneous experimental diabetes are in favor of the first or the second hypothesis. It appears likely that glucagon plays a role in the metabolic derangments of diabetes. Indeed, hepatic glucose production is closely related to the ratio of molar concentrations of insulin and glucagon. Finally, in insulin-dependant diabetics, somatostatin infusion reduces plasma glucagon concentration and blood glucose and prevents the development of ketosis after withdrawal of insulin therapy. These results illustrate the contribution of glucagon in the pathogenesis of hyperglycemia and ketosis. Several arguments have been accumulated in favor of the following concept: diabetes hyperglycemia results both from glucose under-utilization secondary to insulin lack and from hepatic glucose over-production due to glucagon excess. Although controversial, the role of glucagon in ketogenesis appears likely.

To assess the effects of metabolic control upon beta cell function in diabetes, pro-insulin and insulin were determined following gel-filtration of plasma at two time points in each three diabetic patients, once when the metabolic state was severely deranged and again after the metabolic state had improved after therapy. Before therapy, proinsulin concentration were 30 pM (as IRI), both fasting and at 2 hours after an oral glucose load. These values did not change with treatment. Insulin concentrations were 22 pM at both time points before therapy. With treatment, plasma insulin increased 2-fold at fasting and 7-fold at 2 hours after oral glucose. These results suggest an exhaustion of the insulin pool in beta cells during severe metabolic decompensation of diabetes, a condition which may be reversed by correction of the metabolic states of the patients with proper therapy.

Insulin binding to receptors on erythrocytes was studied in patients with acromegaly (n = 27) and in control subjects without any endocrine pathology, diabetes or obesity (n = 13). According to fasting serum concentration of growth hormone (GH), acromegalics were divided into two groups: A) GH less than 10 ng/ml (n = 16) and B) GH above 20 ng/ml (n = 11), in which patients were further divided into subgroups with regard to the presence or absence of diabetes. Insulin binding was decreased both in active and inactive acromegalics when compared with controls. A greater decrease was seen in active acromegaly coupled with diabetes. This was not the case of inactive hyperglycaemic acromegalics, where a compensatory increase in the affinity of "empty" receptors might account for a lack of a greater decrease in insulin binding.