Glycemic control and cancer outcomes in oncologic patients with diabetes: an Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE), Italian Society of Pharmacology (SIF) multidisciplinary critical view.

BACKGROUND:  Increasing evidence suggests that diabetes increases the risk of developing different types of cancer. Hyperinsulinemia, hyperglycemia and chronic inflammation, characteristic of diabetes, could represent possible mechanisms involved in cancer development in diabetic patients. At the same time, cancer increases the risk of developing new-onset diabetes, mainly caused by the use of specific anticancer therapies. Of note, diabetes has been associated with a ∼10% increase in mortality for all cancers in comparison with subjects who did not have diabetes. Diabetes is associated with a worse prognosis in patients with cancer, and more recent findings suggest a key role for poor glycemic control in this regard. Nevertheless, the association between glycemic control and cancer outcomes in oncologic patients with diabetes remains unsettled and poorly debated. PURPOSE:  The current review seeks to summarize the available evidence on the effect of glycemic control on cancer outcomes, as well as on the possibility that timely treatment of hyperglycemia and improved glycemic control in patients with cancer and diabetes may favorably affect cancer outcomes.

Diabetes and work: The need of a close collaboration between diabetologist and occupational physician.

AIM: The Italian Society of Occupational Medicine (SIML), the Italian Diabetes Society (SID) and the Association of Diabetologists (AMD) joined a working group that produced a consensus paper aimed to assess the available evidence regarding the interplay between specific working conditions, including shift- and night-time work, working activities at high risk of accidents and work at heights, working tasks requiring high-energy expenditure, working activities at extreme temperatures and diabetes. DATA SYNTHESIS: Diabetes is a group of metabolic disorders caused by defects in insulin secretion and/or action affecting millions of people worldwide, many of whom are or wish to be active members of the workforce. Although diabetes, generally, does not prevent a person from properly performing his/her working tasks, disease complications can significantly compromise a person's ability to work. Therefore, it appears evident the need to understand the relationship between occupational risk factors and diabetes. The working group included in the document some practical recommendations useful to ensure diabetic workers the possibility to safely and effectively undertake their jobs and to adequately manage and treat their disease, also in the workplace. In this perspective concerted action of all the workplace preventive figures, occupational physicians and diabetologists should be strongly encouraged. CONCLUSIONS: Further studies are necessary to define workplace-based interventions, which should be minimally invasive towards the work organization, allowing diabetic workers to fully realize their work skills while improving their wellbeing at work.

Long-acting insulin analogs and cancer.

AIMS: Hyperinsulinemia is a recognized risk factor for cancer and plays a major role for the increased cancer incidence in diabetic patients. Whether insulin analogs, and particularly long-acting analogs, worsen the pro-cancer effect of excess insulin is still controversial. DATA SYNTHESIS: In this paper we summarize the biological bases for the potential detrimental effect of long-acting analogs on cancer cells and review the in vitro and in vivo evidence on this issue. Because of their different molecular structure relative to native insulin, insulin analogs may activate the insulin receptor (IR) and the post receptor pathways differently. Most, but not all, in vitro evidence indicate that long-acting analogs may have a stronger mitogenic potency than insulin on cancer cells. Notably insulin glargine, the most studied long-acting analog, also has a higher affinity for the insulin-like growth factor (IGF)-1 receptor, a potent growth mediator. In vitro observations, however, may not reflect what occurs in vivo when analogs are metabolized to derivatives with a different mitogenic activity. Clinical studies, mostly retrospective and predominantly concerning glargine, provide contrasting results. The only perspective trial found no cancer increase in patients treated with glargine. All these studies, however, have severe weaknesses because of the insufficient evaluation of important factors such as dose administered, length of exposure, patient follow-up duration and site-specific cancer investigation. Moreover, whether cancer promotion is a long-acting analog class characteristic or a specific effect of a single agent is not clear. CONCLUSIONS: In conclusion the carcinogenic risk of long-acting analogs, and specifically glargine, can be neither confirmed nor excluded. A personalized and shared decision, considering all the individual risk factors (metabolic and non-metabolic), is the suggestion for the clinician.

Abnormal 1-hour post-load glycemia during pregnancy impairs post-partum metabolic status: a single-center experience.

PURPOSE: Recent evidence indicates that people with normal glucose tolerance (NGT) but 1-h post-load plasma glucose (1-h OGTT) ≥ 155 mg/dl have an increased risk for developing Type 2 diabetes mellitus (T2DM), determining a new risk category with deeper metabolic impairment. The aim of this study was to identify, among women with gestational diabetes (GDM), which alterations at OGTT during pregnancy are more frequently associated with 1-h OGTT ≥ 155 mg/dl at post-partum examination. METHODS: Among 297 women affected by GDM, we retrospectively evaluated 244 resulted NGT after delivery. Based on post-partum glucose levels at 1-h OGTT, these people were divided into 188 cases (77.0%) with 1-h OGTT < 155 mg/dl (L-NGT) and 56 (23.0%) with 1-h OGTT ≥ 155 mg/dl (H-NGT). RESULTS: Abnormal glucose levels at 1-h OGTT during pregnancy (≥ 180 mg/dl) were more frequent in H-NGT than in L-NGT (39.3 vs. 24.6%, odds ratio 3.7 [95% CI 1.4-9.6]; p = 0.016). Moreover, H-NGT showed more frequently the simultaneous alteration of all three OGTT plasma glucose values during pregnancy (10.7 vs. 2.1%, odds ratio 4.5 [95% CI 1.5-20.3]; p = 0.038) and less frequently the alteration of fasting plasma glucose alone (14.3 vs. 30.8%, odds ratio 0.4 [95% CI 0.1-0.7]; p = 0.028). CONCLUSIONS: Abnormal 1-h OGTT during pregnancy predicts an increased risk for post-partum 1-h OGTT ≥ 155 mg/dl in women with previous GDM. Even if NGT after delivery, these women may require a closer long-term post-partum follow-up, being at higher risk to develop future glucose intolerance.

Type 2 diabetic patients with Graves' disease have more frequent and severe Graves' orbitopathy.

BACKGROUND AND AIMS: Due to the worldwide increasing prevalence of diabetes (DM), patients with both diabetes and Graves' disease (GD) have become more frequent. Sporadic reports indicate that Graves' orbitopathy (GO), a GD complication that affects orbital soft tissues, can be severe in DM patients. The relationship between these diseases is not well understood. This study aims at evaluating the association of GD and GO with autoimmune and non-autoimmune diabetes (DM) and to assess diabetic features that influence GD and GO prevalence and severity. METHODS AND RESULTS: This retrospective study evaluated GD, GO and DM association in 1211 consecutive GD patients (447 with GO and 77 with DM). A case-control study was carried out to evaluate DM relationship with GO severity by comparing at 1:2 ratio GO patients with or without DM. A strong association was found between GD and T1DM (p = 0.01) but not T2DM. Instead, the presence of GO was strongly associated with T2DM (p = 0.01). Moreover, GO was more frequently severe in GD patients with T2DM (11/30 or 36.6%) than in those without T2DM (1/60 or 1.7%, p = 0.05). T2DM was the strongest risk factor for severe GO (OR = 34.1 vs. 4.4 p < 0.049 in cigarette smokers). DM duration, obesity and vascular complications, but not metabolic control were significant determinants of GO severity. CONCLUSIONS: GD is associated with T1DM but not with T2DM, probably because of the common autoimmune background. GO, in contrast, is more frequent and severe in T2DM, significantly associated with obesity, diabetes duration and diabetic vasculopathy but not metabolic control.

Clinical and molecular mechanisms favoring cancer initiation and progression in diabetic patients.

Cancer incidence and mortality are higher among diabetic patients. This review examines the mechanisms, both general and site-specific, for this increase. Hyperglycemia and hyperinsulinemia, which are the major abnormalities that characterize diabetes, can promote cancer via both independent and synergic mechanisms. Insulin is both a metabolic hormone and a growth factor that promotes cell proliferation. When insulin levels are increased due to either insulin resistance or insulin treatment, their mitogenic effect is more marked in malignant cells that frequently overexpress the insulin receptor and, more specifically, its A isoform that has predominant mitogenic activity. Hyperglycemia provides energy for malignant cell proliferation and, via the peculiar energy utilization of cancer cells, favors cancer growth and neoangiogenesis. Additionally, diabetes-associated obesity has cancer-promoting effects due to mechanisms that are specific to excess fat cells (such as increased peripheral estrogens, increased pro-mitogen cytokines and growth factors). Also fat-associated chronic inflammation can favor cancer via the cell damage caused by reactive oxygen species (ROS) and via the production of inflammatory cytokines and transcription factors that stimulate cancer growth and invasiveness. Finally, the multiple drugs involved in the treatment of diabetes can also play a role. Diabetes-associated comorbidities, tissue-specific inflammation, and organ-specific dysfunctions can explain why the risk of cancer can differ by tissue type among diabetic patients. The increased risk of cancer-related mortality is moderate among individual patients with diabetes (RR = 1.25), but the pandemic nature of the disease means that a considerable number of lives could be spared through a better understanding of the factors associating diabetes and cancer.

Diabetes management in cancer patients. An Italian Association of Medical Oncology, Italian Association of Medical Diabetologists, Italian Society of Diabetology, Italian Society of Endocrinology and Italian Society of Pharmacology multidisciplinary consensus position paper.

Cancer management has significantly evolved in recent years, focusing on a multidisciplinary team approach to provide the best possible patient care and address the various comorbidities, toxicities, and complications that may arise during the patient's treatment journey. The co-occurrence of diabetes and cancer presents a significant challenge for health care professionals worldwide. Management of these conditions requires a holistic approach to improve patients' overall health, treatment outcomes, and quality of life, preventing diabetes complications and cancer treatment side-effects. In this article, a multidisciplinary panel of experts from different Italian scientific societies provide a critical overview of the co-management of cancer and diabetes, with an increasing focus on identifying a novel specialty field, 'diabeto-oncology', and suggest new co-management models of cancer patients with diabetes to improve their care. To better support cancer patients with diabetes and ensure high levels of coordinated care between oncologists and diabetologists, 'diabeto-oncology' could represent a new specialized field that combines specific expertise, skills, and training.

MiRNA dysregulation underlying common pathways in type 2 diabetes and cancer development: an Italian Association of Medical Oncology (AIOM)/Italian Association of Medical Diabetologists (AMD)/Italian Society of Diabetology (SID)/Italian Society of Endocrinology (SIE)/Italian Society of Pharmacology (SIF) multidisciplinary critical view.

Increasing evidence suggests that patients with diabetes, particularly type 2 diabetes (T2D), are characterized by an increased risk of developing different types of cancer, so cancer could be proposed as a new T2D-related complication. On the other hand, cancer may also increase the risk of developing new-onset diabetes, mainly caused by anticancer therapies. Hyperinsulinemia, hyperglycemia, and chronic inflammation typical of T2D could represent possible mechanisms involved in cancer development in diabetic patients. MicroRNAs (miRNAs) are a subset of non-coding RNAs, ⁓22 nucleotides in length, which control the post-transcriptional regulation of gene expression through both translational repression and messenger RNA degradation. Of note, miRNAs have multiple target genes and alteration of their expression has been reported in multiple diseases, including T2D and cancer. Accordingly, specific miRNA-regulated pathways are involved in the pathogenesis of both conditions. In this review, a panel of experts from the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE), and Italian Society of Pharmacology (SIF) provide a critical view of the evidence about the involvement of miRNAs in the pathophysiology of both T2D and cancer, trying to identify the shared miRNA signature and pathways able to explain the strong correlation between the two conditions, as well as to envision new common pharmacological approaches.

Insulin analogues differently activate insulin receptor isoforms and post-receptor signalling.

AIMS/HYPOTHESIS: Five insulin analogues, with modified insulin-like molecular structures, are currently approved for treating diabetic patients. They activate cell signalling and biological responses via insulin receptor isoforms (IR-A and IR-B), each having specific characteristics for eliciting cell responses. The molecular and biological effects of these analogues on receptor isoforms in comparison to native insulin are not well defined, and their effects on the IGF1 receptor (IGF1R) are controversial. The characterisation of these effects was the aim of the present study. METHODS: Short-acting (insulin lispro [B28Lys,B29Pro human insulin], insulin aspart [B28Asp human insulin], insulin glulisine [B3Lys,B29Glu human insulin]) and long-acting (insulin glargine [A21Gly,B31Arg,B32Arg human insulin], insulin detemir [B29Lys(epsilon-tetradecanoyl),desB30 human insulin]) insulin analogues were studied in three engineered cell models (R(-), IGF1R-deprived mouse fibroblasts transfected with either only human IR-A or IR-B or IGF1R). Receptor binding and phosphorylation, AKT and extracellular signal-regulated kinase (ERK) activation, cell proliferation and colony formation were evaluated after exposing the cells to each analogue and were compared with insulin, IGF1 and the carcinogenic analogue B10Asp. RESULTS: All short-acting insulin analogues produced molecular and biological effects similar but not identical to those of insulin. Relative to insulin, long-acting analogues more strongly activated the ERK pathway via both IR-A and IGF1R as well as increased cell proliferation. At the concentration tested, no analogue (except B10Asp via IR-A) had increased transforming activity. CONCLUSIONS/INTERPRETATION: Cell models that permit comparisons of the activity of insulin to that of insulin analogues via each receptor individually indicate that only minor differences exist between insulin and short-acting analogues. By contrast, long-acting analogues activate the mitogenic signalling pathway more effectively than insulin and cause increased cell proliferation.

Rethinking the Relationship between Insulin and Cancer.

In addition to being a major metabolic hormone, insulin is also a growth factor with a mitogenic effect on all cells, more marked in malignant cells that often overexpress the insulin receptor. In patients with metabolic diseases characterized by hyperinsulinemia (obesity, type 2 diabetes, and metabolic syndrome), the incidence of several types of cancer is increased, as is cancer-related mortality. Because of the worldwide growing prevalence of metabolic diseases and the diffuse use of insulin and its analogs for treating diabetes, the relationship between insulin and cancer has become a clinically relevant issue. Clinical studies have not clarified the degree to which hyperinsulinemia can influence cancer occurrence and prognosis. To better understand this issue, an improved scientific approach is required, with more careful consideration of the mechanisms related to hyperinsulinemia and carcinogenesis.

Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells.

Insulin-like growth factor II (IGF-II) is a peptide growth factor that is homologous to both insulin-like growth factor I (IGF-I) and insulin and plays an important role in embryonic development and carcinogenesis. IGF-II is believed to mediate its cellular signaling via the transmembrane tyrosine kinase type 1 insulin-like growth factor receptor (IGF-I-R), which is also the receptor for IGF-I. Earlier studies with both cultured cells and transgenic mice, however, have suggested that in the embryo the insulin receptor (IR) may also be a receptor for IGF-II. In most cells and tissues, IR binds IGF-II with relatively low affinity. The IR is expressed in two isoforms (IR-A and IR-B) differing by 12 amino acids due to the alternative splicing of exon 11. In the present study we found that IR-A but not IR-B bound IGF-II with an affinity close to that of insulin. Moreover, IGF-II bound to IR-A with an affinity equal to that of IGF-II binding to the IGF-I-R. Activation of IR-A by insulin led primarily to metabolic effects, whereas activation of IR-A by IGF-II led primarily to mitogenic effects. These differences in the biological effects of IR-A when activated by either IGF-II or insulin were associated with differential recruitment and activation of intracellular substrates. IR-A was preferentially expressed in fetal cells such as fetal fibroblasts, muscle, liver and kidney and had a relatively increased proportion of isoform A. IR-A expression was also increased in several tumors including those of the breast and colon. These data indicate, therefore, that there are two receptors for IGF-II, both IGF-I-R and IR-A. Further, they suggest that interaction of IGF-II with IR-A may play a role both in fetal growth and cancer biology.

Insulin receptor activation by IGF-II in breast cancers: evidence for a new autocrine/paracrine mechanism.

IGF-II, produced by breast cancer epithelial and stromal cells, enhances tumor growth by activating the IGF-I receptor (IGF-I-R) via autocrine and paracrine mechanisms. Previously we found that the insulin receptor (IR), which is related to the IGF-I-R, is overexpressed in breast cancer cells. Herein, we find that, in breast cancer the IR is activated by IGF-II. In eight human breast cancer cell lines studied there was high affinity IGF-II binding to the IR, with subsequent IR activation. In these lines, IGF-II had a potency up to 63% that of insulin. In contrast, in non malignant human breast cells, IGF-II was less than 1% potent as insulin. Via activation of the IR tyrosine kinase IGF-II stimulated breast cancer cell growth. Moreover, IGF-II also activated the IR in breast cancer tissue specimens; IGF-II was 10-100% as potent as insulin. The IR occurs in two isoforms generated by alternative splicing of exon 11; these isoforms are IR-A (Ex11-) and IR-B (Ex11+). IR-A was predominantly expressed in breast cancer cells and specimens and the potency of IGF-II was correlated to the expression of this isoform (P<0.0001). These data indicate, therefore, that the IR-A, which binds IGF-II with high affinity, is predominantly expressed in breast cancer cells and represents a new autocrine/paracrine loop involved in tumor biology.

Measurement of IGF-1 Receptor Content in Tissues and Cell Lines by Radioimmunoassay (RIA) and ELISA Techniques.

The IGF-1 receptor (IGF-1-R) belongs to the tyrosine kinase growth factor receptor family. It is structurally similar to, but distinct from, the insulin receptor, with which it shares a 70% homology. As expected, it crossreacts with insulin and, vice versa, insulin receptor crossreacts with IGF-1. Numerous studies suggest that IGF-1-R is very important for mitogenesis and is essential for phenotype transformation, at least in rodents (1). In particular, the IGF-1-R has been described in human breast cancer (2-4) and ovarian cancer (5) tissues and in cultured human breast cancer cell lines (6,7).

Quality of Life, Wishes, and Needs in Women with Gestational Diabetes: Italian DAWN Pregnancy Study.

The DAWN (Diabetes Attitudes, Wishes and Needs) study is a survey promoted by the International Diabetes Federation to recognize the perceptions and attitudes of people suffering from diabetes mellitus. In this context, we evaluated the quality of life of Italian and immigrant women with gestational diabetes mellitus (GDM). Information was gathered using a structured questionnaire for patients' self-compilation. In a 3-month period, a 51-item questionnaire was submitted to 198 Italians and 88 immigrants (from 27 different foreign nationalities). Italian women were older and had higher education than the immigrants. 60% of the Italians and 38% of the immigrants had a family history of diabetes mellitus. In both groups, the diagnosis of GDM caused anxiety; one-third of women feared their child could contract diabetes at delivery and/or have congenital malformations. Some women had trouble in following treatment regimens: the major concern being dietary advice and blood glucose testing. Most women were satisfied (34%) or highly satisfied (60%) with the quality of care, although the degree of cooperation between diabetes specialists and gynaecologists was considered sometimes unsatisfactory. In order to optimize maternal and foetal outcomes, educational projects and improved communication between patients and the healthcare provider team are recommended.

Insulin and its analogs: actions via insulin and IGF receptors.

Insulin analogs are artificially modified insulin molecules that allow better metabolic controls of diabetes through either more rapid or more prolonged activity. The interaction of insulin analogs with the insulin receptor isoforms (IR-A and IR-B) and with the IGF-I receptor (IGF-IR) is similar but not identical to that of insulin, and therefore, their biological effects do not always reproduce insulin actions in terms of quantity, quality and timing. Studies on in vitro models indicate that short-acting analogs elicit molecular and biological effects that are similar, but not identical, to those of insulin via IR-A, IR-B and IGF-IR. In contrast, long-acting analogs behave in a more different way relative to insulin. Although data are not homogeneous and observations on the more recently introduced detemir are scarce, both glargine and detemir often show a decreased binding to IR and increased binding to IGF-IR. Also, intracellular signaling is different with respect to insulin, with a prevalent activation of the ERK rather than the AKT pathway. Finally, an increased mitogenic response has often been observed with these analogs in a variety of cell models. Of course, in vitro studies do not necessarily reflect what occurs in patients, due to the different metabolism of analogs in vivo and their interaction with components of the extracellular environment. After many years of analog's use, observations in patients indicate that insulin analogs are both effective and safe. Prospective clinical studies, however, may add further useful information on the issue of the insulin analogs' possible differences with respect to native insulin.

Frizzled-1 is down-regulated in follicular thyroid tumours and modulates growth and invasiveness.

The mechanisms of follicular thyroid carcinoma (FTC) transformation and progression are not well understood. Previously, we detected LOH at 7q21 in all FTCs examined, indicating that loss of genetic material in that region is a common trait in these lesions. To analyse the effects of LOH on gene expression, we performed an analysis of the mRNA expression levels of six different genes, located at 7q21.1-7q21.3. A total of 23 lesions, including eight follicular hyperplasias (FHs), eight follicular adenomas (FAs), two FTCs and five papillary thyroid carcinomas (PTCs) were analysed. The Frizzled-1 (FZD-1) gene, located at 7q21.13, showed the lowest levels of mRNA expression. Down-regulation of FZD-1 expression was also confirmed in an independent series of 69 follicular neoplastic lesions compared to 25 PTCs, analysed by quantitative RT-PCR. In vitro studies showed that FZD-1 expression was also markedly reduced at both protein and mRNA levels in three FTC-derived cell lines (FRO, WRO and FTC-133), while it was normal in the three PTC-derived cell lines (Ca300, Ca301 and K1) examined. We demonstrated that over-expression of FZD-1 in 3 FTC-derived cells decreased invasiveness and proliferation rate, indicating a possible pathogenetic role. In addition, FZD-1 RNA interference in the PTC-derived cell line K1 increased invasiveness. Our data indicated that FZD-1 is involved in growth of follicular tumours and may be considered as a novel marker of this type of tumour.