Pasquale Vitale

Pathophysiology of Diabetes Mellitus in Cushing's Syndrome

Cushing’s syndrome is commonly complicated with an impairment of glucose metabolism, which is often clinically manifested as diabetes mellitus. The development of diabetes mellitus in Cushing’s syndrome is both a direct and indirect consequence of glucocorticoid excess. Indeed, glucocorticoid excess induces a stimulation of gluconeogenesis in the liver as well as an inhibition of insulin sensitivity both in the liver and in the skeletal muscles, which represent the most important sites responsible for glucose metabolism. In particular, glucocorticoid excess stimulates the expression of several key enzymes involved in the process of gluconeogenesis, with a consequent increase of glucose production, and induces an impairment of insulin sensitivity either directly by interfering with the insulin receptor signaling pathway or indirectly, through the stimulation of lipolysis and proteolysis and the consequent increase of fatty acids and amino acids, which contribute to the development of insulin resistance. Moreover, the peculiar distribution of adipose tissue throughout the body, with the predominance of visceral adipose tissue, significantly contributes to the worsening of insulin resistance and the development of a metabolic syndrome, which participates in the occurrence and maintenance of the impairment of glucose tolerance. Finally, glucocorticoid excess is able to impair insulin secretion as well as act at the level of the pancreatic beta cells, where it inhibits different steps of the insulin secretion process. This phenomenon is probably responsible for the passage from an impairment of glucose tolerance to an overt diabetes mellitus in susceptible patients with Cushing’s syndrome.

Cardiovascular Disease in Cushing’s Syndrome: Heart versus Vasculature

Cushing’s syndrome (CS) causes metabolic abnormalities that determine an increased cardiovascular risk not only during the active phase of the disease but also for a long time after cure. Cardiovascular complications, such as premature atherosclerosis, coronary artery disease, heart failure, and stroke, in patients with CS cause a mortality rate higher than that observed in a normal population. The increased cardiovascular risk is mainly due to metabolic complications, such as metabolic syndrome, but also to vascular and cardiac alterations such as atherosclerosis and cardiac structural and functional changes. In the clinical management of patients with CS the focus should be on identifying the global cardiovascular risk and the aim should be to control not only hypertension but also other correlated risk factors, such as obesity, glucose intolerance, insulin resistance, dyslipidemia, endothelial dysfunction and the prothrombotic state. Considering that remission from hypercortisolism is often difficult to achieve and that the cardiovascular risk can persist even during disease remission, care and control of all cardiovascular risk factors should be one of the primary goals during the follow-up of these patients.

Effect of Cabergoline on Metabolism in Prolactinomas

Introduction: Hyperprolactinemia has been implicated in the pathogenesis of obesity and glucose intolerance and is reportedly associated with an impaired metabolic profile. The current study aimed at investigating the effects of 12- and 60-month treatment with cabergoline (CAB) on metabolic syndrome (MetS) in patients with prolactinomas. Patients and Methods: 61 patients with prolactinomas (13 men, 48 women, 41 with microadenoma, 20 with macroadenoma), aged 34.4 ± 10.3 years, entered the study. In all patients, prolactin (PRL) and metabolic parameters were assessed at diagnosis and after 12 and 60 months of continuous CAB treatment. MetS was diagnosed according to NCEP-ATP III criteria. Results: Compared to baseline, CAB induced a significant decrease in PRL with complete normalization in 93% of patients after the 60-month treatment. At baseline, MetS prevalence was significantly higher in patients with PRL above (34.5%) than in those with PRL lower (12.5%) than the median (129 μg/l, p = 0.03). MetS prevalence significantly decreased after 12 (11.5%, p = 0.039) and 60 (5.0%, p = 0.001) months compared to baseline (28.0%). At both evaluations the lipid profile significantly improved compared to baseline. Fasting insulin and homeostatic model assessment of insulin resistance significantly decreased after 1 year of CAB (p = 0.012 and p = 0.002, respectively) and further improved after 60 months (p = 0.000). The visceral adiposity index significantly decreased after the 60-month treatment (p = 0.000) compared to baseline. At the 5-year evaluation CAB dose was the best predictor of percent decrease in fasting insulin (t = 2.35, p = 0.022). Conclusions: CAB significantly reduces MetS prevalence and improves the adipose tissue dysfunction index. The improvement in PRL, insulin sensitivity and other metabolic parameters might reflect the direct effect of CAB.

The kidney in acromegaly: renal structure and function in patients with acromegaly during active disease and 1 year after disease remission

BACKGROUND The GH/insulin-like growth factor 1 axis is physiologically involved in the regulation of electrolytes and water homeostasis by kidneys, and influences glomerular filtration and tubular re-absorption processes. The aim of the study was to investigate renal structure and function in acromegalic patients during active disease and disease remission. PATIENTS Thirty acromegalic patients (15 males and 15 females), aged 32-70 years, were enrolled for the study. Ten de novo patients had active disease, whereas 20 patients showed disease remission 1 year after medical treatment with somatostatin analogs (SA) (ten patients) or surgery (ten patients). Thirty healthy subjects matched for age, gender, and body surface area were enrolled as controls. RESULTS In both active (A) and controlled (C) patients, creatinine clearance (P<0.001) and citrate (P<0.05) and oxalate levels (P<0.001) were higher, whereas filtered Na (P<0.001) and K (P<0.001) fractional excretions were lower than those in the controls. Urinary Ca (P<0.001) and Ph (P<0.05) levels were significantly increased compared with the controls, and in patients with disease control, urinary Ca (P<0.001) levels were significantly reduced compared with active patients. Microalbuminuria was significantly increased in active patients (P<0.05) compared with controlled patients and healthy control subjects. The longitudinal (P<0.05) and transverse (P<0.05) diameters of kidneys were significantly higher than those in the controls. In all patients, the prevalence of micronephrolithiasis was higher than that in the controls (P<0.001), and was significantly correlated to disease duration (r=0.871, P<0.001) and hydroxyproline values (r=0.639, P<0.001). CONCLUSIONS The results of the current study demonstrated that acromegaly affects both renal structure and function. The observed changes are not completely reversible after disease remission.

Complete disappearance of a GH-secreting pituitary macroadenoma in a patient with acromegaly: effect of treatment with lanreotide Autogel and consequence of treatment withdrawal

BACKGROUND Somatostatin analogs (SA) are the cornerstone in the medical treatment of acromegaly, used as either primary or adjunctive therapy. In particular, SA are effective in inducing the biochemical remission of the disease and tumor shrinkage, although only few cases of complete disappearance of the pituitary tumor in patients treated with SA as long-acting formulations have been reported. SA withdrawal has been demonstrated to keep safe levels of GH and IGF1 at least in a small subset of patients well responsive to SA, although it is generally followed by disease recurrence after several months. CASE REPORT A 61-year-old female patient bearing a very large GH-secreting pituitary macroadenoma was treated with 12-month lanreotide Autogel (ATG), at the initial dose of 120 mg/28 days. After 3 months, GH and IGF1 levels were fully normalized, to prolong the administration interval from 28 to 56 days. After 6 months of treatment, a significant tumor shrinkage (90% of baseline size) was observed, whereas GH and IGF1 excess was still well controlled. After 12-month therapy, a complete disappearance of the pituitary tumor was observed, and the hormonal evaluation confirmed the complete biochemical remission of acromegaly. Lanreotide ATG treatment was withdrawn. The clinical, biochemical, and radiological remission of acromegaly was maintained 24 months after lanreotide ATG treatment discontinuation, without evidence of disease recurrence. CONCLUSIONS This report represents an exemplary case of the potentiality of treatment with lanreotide ATG in inducing a complete remission of acromegalic disease, persistent after a long period of time from treatment withdrawal.

Effect of Chronic Cabergoline Treatment and Testosterone Replacement on Metabolism in Male Patients with Prolactinomas

Introduction: Hyperprolactinemia and hypogonadism are reportedly associated with an impaired metabolic profile. The current study aimed at investigating the effects of testosterone replacement and cabergoline (CAB) treatment on the metabolic profile in male hyperprolactinemic patients. Patients and Methods: Thirty-two men with prolactinomas, including 22 with total testosterone (TT) <8 nmol/l (HG, 69%) and 10 with TT >8 nmol/l (non-HG, 31%), were entered in the study. In all patients, metabolic parameters were assessed at diagnosis and after 12- and 24-month treatment. Results: Compared to non-HG patients, at baseline the HG patients had higher waist circumference (WC). TT significantly correlated with body mass index (BMI). Twelve-month CAB induced PRL normalization in 84%. HG prevalence significantly decreased (28%) and non-HG prevalence significantly increased (72%). Anthropometric and lipid parameters, fasting insulin (FI), insulin sensitivity index (ISI₀), homeostatic model assessment of insulin secretion (HOMA-β) and homeostatic model assessment of insulin resistance (HOMA-IR) significantly improved compared to baseline. TT was the best predictor for FI. Percent change (Δ) of TT significantly correlated with ΔCholesterol, ΔWeight and ΔBMI. Compared to non-HG patients, the HG patients had a higher weight, BMI, WC and HOMA-β. In HG, testosterone replacement was started. After 24 months, PRL normalized in 97%. HG prevalence significantly decreased (6%) and non-HG prevalence significantly increased (94%). Anthropometric and lipid parameters, FI, ISI₀, HOMA-β and HOMA-IR significantly improved compared to baseline, with FI, ISI₀, HOMA-β and HOMA-IR further ameliorating compared to the 12-month evaluation. Compared to non-HG patients, the HG patients still had a higher weight, BMI and WC. Conclusions: In hyperprolactinemic hypogonal men, proper testosterone replacement induces a significant improvement in the metabolic profile, even though the amelioration in the lipid profile might reflect the direct action of CAB.

Diabetes and Cancer

The hypothesis that diabetes mellitus (DM) is associated with an increased risk of cancer is a deep-rooted suggestion, formulated probably during nineteenth century, surely very far away from knowledge of the pathogenic mechanisms of both diseases. Nowadays, numerous meta-analysis demonstrate the strong positive correlation existing between DM and site-specific cancer. In addition, patients developing cancer with pre-existing DM are reported to experience higher short- and long-term mortality. Anyway, the increased risk of cancer development in subjects with an alteration of glucose metabolism is not yet explained: this lack could be addressed to the overlapping risk factors of both diseases like physical inactivity and overalimentation or to the confounding factor represented by anti-diabetic treatments. The strongest association between DM and site-specific cancer regards liver and pancreatic cancer. Liver cells are exposed to high levels of insulin and, consequently, to its mitogenic effect due to portal circulation. However, this event occurs both in diabetic and non-diabetic subjects, so limiting the relevance of this mechanism to explain the high frequency of liver cancer in DM. On the other hand, diabetic patients are more prone to develop cirrhosis, steatosis, and non-alcoholic fatty liver disease (NAFLD) and these conditions are surely correlated to liver cancer. The relationship between DM and pancreatic cancer is very difficult to prove because it is arduous to establish which condition begins firstly between cancer or hyperglycemia (like the question of the chicken and the egg). However, lots of reported findings give support to consider DM as risk factor for pancreatic cancer; actually, deeper researches are necessary to clarify the mechanism and the implication of this intriguing connection. Another of the main site-specific cancer frequently associated with DM is breast cancer (BC), the most common cause of death due to cancer in European women. Around one in five women with BC is affected also by DM and probably their coexistence could be explained by similar risk factors like obesity, dyslipidemia, and hyperinsulinemia, although the mechanism underlying this articulated relation needs to be clarify. Several longitudinal and retrospective cohort studies demonstrate that the frequency of BC is significantly increased in postmenopausal women with DM; furthermore, they reveal that the prognosis of women with BC and DM is worse and overall mortality is higher in comparison with non-diabetic patients. An increase of the development of other organ cancers in correlation with DM is reported, although in some cases studies are not so numerous or well built. They include endometrial, colorectal, and bladder cancer in which the most recent evidence underline not only a raise in the prevalence in the cohort of patients with DM but also an increased mortality. As all the rules that must be respected, the positive correlation between DM and cancer has an exception represented by prostate cancer. In contrast with the other evidences, in fact, recent meta-analysis report a reduced frequency of prostate cancer in men affected by DM. Even though insulin can play a role also in the progression and the prognosis of this specific cancer, especially during the androgen deprivation therapy, diabetes-related hypogonadism seems to represent the pivotal determining of the decreased risk of developing this neoplasm. Focusing on the possible pathogenic mechanism that sustained this linkage, the metabolic disequilibrium that characterize a diabetic person contains various elements of interest able to explain several aspects of the increased risk of neoplasm or tumoral progression in these patients. These are represented by hyperglycemia, hyperinsulinemia and insulin resistance, obesity and chronic inflammation which are singularly or contemporary present in DM. By definition, cancer cells have a very sustained proliferation and need more glucose than other cells; DM and correlated hyperglycemia are optimal conditions for sustaining this metabolic change occurring in cancer cells, that, opportunely, increase the expression of glucose membrane transporters. This abnormal activation of glucose catabolism leads to an increased production of lactate that reduced ph of extracellular matrix, causing the death of non-tumoral cells and promoting the activation of matrix collagenases which make easier the development of metastasis. In addition, hyperglycemia cause the accumulation of advanced glycation end-products (AGEs) which are responsible for oncogenic DNA damaging through the production of reactive oxygen species (ROS). In non-type I DM, insulin levels are almost always elevated upon the upper range limit and it is associated with the intensification of its pro-proliferative effect. Several studies in literature confirm the mitogenic effect of insulin that could be considered as a peculiar growth factor; this peculiarity became stronger if we consider that insulin can activate non-only its proper receptor (IR), which results in anti-apoptotic activities, but also insulin-like growth factor 1 receptor (IGF-1R) whose pathway play an essential role in cell multiplication and immortalization. The importance of the function of insulin in the development of cancer in diabetic patients is confirmed by the significantly increased expression of IR and IGF-1R in tumoral cells. A significant percentage of patients affected by DM has a BMI compatible with the diagnosis of obesity. Apart from the induced hyperinsulinemia and insulin resistance, typical in these patients, peptide hormones secreted by adipose tissue can represent the keystones to explain the mechanism by which obesity favors cancer in diabetic patients. Adiponectin and leptin are in fact probably involved in regulating carcinogenesis; the first has an anti-inflammatory activity and stimulate the glucose metabolism, increasing the insulin sensitivity. Leptin, on the other hand, is been demonstrated having a pro-inflammatory effect which finally results in the stimulation of neoplastic transformation, cell proliferation, and neo-angiogenesis. The multiform relation between DM and cancer is far away to be definitively understood and all the studies of the next years will have to reckon with the complexity of both DM and neoplasms and consider the heterogeneity of the population involved. But, in the third millenium medicine, all the scientist are called to make an effort in order to give a solution to the emerging health questions of our society. This is the mission they are expected to accomplish. I am hopeful.

Contents Vol. 98, 2013

D.H. Abbott, Madison, Wisc. E. Arzt, Buenos Aires A.V. Babwah, London, Ont. T. Bartness, Atlanta, Ga. C.L. Bethea, Beaverton, Oreg. D.W. Brann, Augusta, Ga. B. Canny, Monash, Vic. M. Caplin, London K. Catt, Bethesda, Md. A. Chodobski, Providence, R.I. S.L. Dickson, Gothenburg J. Drouin, Montreal, Que. P.J. Enriori, Monash, Vic. W. Farrell, Keele M. Freeman, Tallahassee, Fla. A.C. Gore, Austin, Tex. K. Grove, Beaverton, Oreg. T. Harmar, Edinburgh A. Herbison, Dunedin J. Herman, Cincinnati, Ohio J.J. Hirst, Callaghan, N.S.W. T. Hökfelt, Stockholm U. Kaiser, Boston, Mass. G. Kaltsas, Athens K. Kim, Seoul J.Z. Kiss, Geneva A.C. Latronico, São Paulo G. Leng, Edinburgh J. Levine, Evanston, Ill. C. Libertun, Buenos Aires C. Llorens-Cortes, Paris A. Lomniczi, Beaverton, Oreg. A. Loudon, Manchester Z.-L. Lu, Edinburgh G. Martinez de la Escalera, Querétaro R. Melcangi, Milano I. Modlin, New Haven, Conn. Z. Naor, Tel Aviv M. Palkovits, Budapest I. Parhar, Kuala Lumpur D.W. Pfaff , New York, N.Y. T.M. Plant, Pittsburgh, Pa. J. Reul, Bristol R. Reynolds, Edinburgh E. Rissman, Charlottesville, Va. J.L. Roberts, San Antonio, Tex. I. Robinson, London P. Ruszniewski, Clichy W. Schlegel, Geneva D. Skinner, Laramie, Wyo. M. Sleeman, Clayton, Vic. J. Smith, Perth, W.A. E. Spinedi, La Plata R. Steiner, Seattle, Wash. E. Terasawa, Madison, Wisc. A. Tilbrook, Roseworthy, S.A. B. Walker, Edinburgh H. Watanobe, Chiba M. Watt, Clayton, Vic. K. Weston-Green, Wollongong, N.S.W. M.E. Wierman, Aurora, Colo. J. Wingfi eld, Seattle, Wash. S. Wray, Bethesda, Md. International Journal for Basic and Clinical Studies on Neuroendocrine Relationships