insulin-glargine and Hyperinsulinism

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.. 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.. 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.

Topics: Animals; Biomarkers; Blood Glucose; Clinical Decision-Making; Diabetes Mellitus; Humans; Hyperinsulinism; Hypoglycemic Agents; Incidence; Insulin Glargine; Neoplasms; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome

The relationship between diabetes and pancreatic cancer is complex. Diabetes or impaired glucose tolerance is present in more than 2/3rd of pancreatic cancer patients. Epidemiological studies have consistently shown a modest increase in the risk of pancreatic cancer in type 2 diabetes, with an inverse relationship to duration of disease. Additionally, recent studies suggest that anti-diabetic medications may modulate the risk of pancreatic cancer in type 2 diabetes. Subjects >50 years of age with new onset diabetes are at higher risk of having pancreatic cancer. However, to screen new-onset diabetes for pancreatic cancer, additional markers are needed that can distinguish pancreatic cancer-associated diabetes from type 2 diabetes.

Topics: Age Factors; Body Mass Index; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Early Detection of Cancer; Evidence-Based Medicine; Global Health; Glucose Intolerance; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Meta-Analysis as Topic; Metformin; Obesity; Pancreatic Neoplasms; Prevalence; Risk Assessment; Risk Factors

To give an overview on the relationship between diabetes mellitus and increased cancer risk.. We identified studies evaluating the association between diabetes mellitus, its treatment with insulin and insulin analogues and malignancies, paying special attention to studies on in vitro and in vivo effects of the long-acting analogue insulin glargine.. Even although the pathophysiological mechanisms underlying the relationship between elevated cancer risk and Type 2 diabetes mellitus are not completely understood, hyperinsulinaemia in the presence of insulin resistance appears to be a key factor. Because of the mitogenic actions of insulin at high concentrations, hyperinsulinaemia may favour tumorigenesis. In line with this, an insulin-based therapy is associated with an increased cancer risk, whereas an insulin-sensitizing treatment results in a cancer risk reduction. Furthermore, alterations of the insulin receptor profile on tumour cells may contribute to an enhanced susceptibility towards insulin. Studies on the analogue insulin glargine have been controversial. In vitro data pointed to an elevated mitogenicity of insulin glargine, whereas in vivo data did not confirm cancerogenous effects. Moreover, recently published clinical studies on the association of insulin glargine (Lantus®) and cancer suggest that treatment with insulin glargine is not associated with increased cancer risk.. The relationship between elevated cancer risk and Type 2 diabetes mellitus has been shown by numerous epidemiological studies, with endogenous and exogenous hyperinsulinaemia in the presence of insulin resistance as potential underlying pathophysiological mechanisms. Recent clinical studies do not support an increased cancer risk in patients treated with insulin glargine.

Topics: Diabetes Mellitus, Type 2; Female; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Male; Neoplasms; Risk Factors

Type 2 diabetes mellitus and malignant tumors are frequent diseases worldwide. The incidence of these two diseases is growing continuously and causes serious health care problem. Population based epidemiologic studies show that the coexistence of type 2 diabetes and malignant tumors is more frequent than expected by the age-corrected incidence and prevalence of each disease. Epidemiologic studies and meta-analyses show that type 2 diabetes increases the risk and tumor specific mortality of certain cancers. The overlapping risk factors of the diseases suggest a relationship between type 2 diabetes and malignant tumors, with a significant role of obesity as a major risk factor. In the pathophysiology of type 2 diabetes there are several biological processes, which may explain the higher cancer risk in type 2 diabetes. In vitro experiments, and in vivo animal studies show that the mitotic effect of hyperinsulinemia plays an important role in the relationship of cancer and type 2 diabetes mellitus. Recent studies show that the different treatment modalities, antidiabetic drugs and their combinations used for the treatment of type 2 diabetes can modify cancer risk. The majority of the data show that metformin therapy decreases, while insulin secretagog drugs slightly increase the risk of certain types of cancers in type 2 diabetes. Metformin can decrease cell proliferation and induce apoptosis in certain cancer cell lines. Endogenous and exogenous (therapy induced) hyperinsulinemia may be mitogenic and may increase the risk of cancer in type 2 diabetes. Human studies showed that the analogue insulin glargin increases the risk of certain cancers. As a result of conceptual weaknesses in study design, data collection, and statistical methods the results of these studies are questionable. According to present knowledge, obtaining and maintaining optimal metabolic target values with the appropriate choice of treatment modality is the aim of treatment in type 2 diabetes. Presently, study results showing elevated mitogenic potential with some antidiabetic treatment modalities are not taken into account, when considering the choice of antidiabetic treatment in type 2 diabetic patients. In the care of patients with increased cancer risk, oncologic considerations should be taken into account. Well designed, prospective, clinical studies would be necessary to demonstrate the possible correlation between treatment modalities of type 2 diabetes and change of cancer risk in

Topics: Adipokines; Age Factors; Animals; Cytokines; Diabetes Complications; Diabetes Mellitus, Type 2; Feeding Behavior; Humans; Hyperglycemia; Hyperinsulinism; Hypoglycemic Agents; Incidence; Insulin; Insulin Glargine; Insulin Resistance; Insulin, Long-Acting; Metformin; Motor Activity; Neoplasms; Obesity; Prevalence; Research Design; Risk Factors; Sex Factors; Smoking; Sulfonylurea Compounds; Thiazolidinediones

Numerous epidemiological studies have demonstrated an association between increased risk of cancer development and progression and type 2 diabetes mellitus as well as obesity. The underlying mechanisms remain elusive, but hyperinsulinaemia in the presence of insulin resistance appears to be an important factor. Hyperinsulinaemia may favour tumorigenesis, as insulin has not only metabolic actions, but is also mitogenic at high concentrations. Besides, susceptibility of tumour cells against insulin may be increased due to changes in the insulin receptor profile. A diabetes therapy with insulin or sulfonylureas, which leads to elevated exogenous or endogenous insulin levels, appears to be related with an increased cancer risk, whereas administration of metformin or thiazolidinediones, which is associated with a decrease of insulin concentrations, results in risk reduction. However, in light of the numerous epidemiological studies showing an association between increased cancer risk and reduced physical activity one cannot exclude that hyperinsulinaemia in the presence of insulin resistance is only a surrogate parameter of reduced physical activity. In the past years, several insulin analogues have been developed which may have altered mitogenic actions compared to human insulin due to their structural changes. For the long-acting analogue insulin glargine, in vitro data, though controversial, pointed to an increased mitogenicity that was, however, not confirmed by in vivo studies. Recently, six clinical studies have been published that analysed the association between the application of insulin glargine (Lantus) and cancer development. The current clinical data do not allow the conclusion that treatment with insulin glargine is associated with increased cancer risk. On the other hand, prospective studies that exclude an impact on cancer risk in risk populations are currently not available. Future studies are required to investigate whether a subpopulation characterised by a less rapid metabolization of insulin glargine in vivo may be at increased cancer risk. In the present article, we give an overview on the association between diabetes mellitus, its treatment with insulin analogues, and cancer.

Topics: Diabetes Mellitus, Type 2; Exercise; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin Resistance; Insulin, Long-Acting; Mutagenicity Tests; Neoplasms; Obesity; Risk Factors

Glargine, a product of recombinant technology, has different structural and physicochemical properties compared with native human insulin. We determined whether such differences are associated with alterations in the responses to hypoglycaemia induced by glargine.. Nineteen adults (six healthy and 13 with type 1 diabetes) underwent a 5-h hyperinsulinaemic (2 mU/kg/min(-1)) stepped hypoglycaemic clamps (hourly targets of 4.7, 4.2, 3.6, 3.1 and 2.5 mmol/l, respectively) on two occasions using intravenous infusion of regular human insulin or glargine, in random sequence. Hypoglycaemic symptoms, counter-regulatory hormones and glucose disposal rates were assessed at intervals throughout the clamps. A 1-week 'wash out' period was observed between studies.. The peak total symptoms scores (mean +/- s.e.m.) at nadir blood glucose (2.5 mmol/1) were 18.83 +/- 2.68 (healthy) and 17.46 +/- 3.62 (diabetic) during regular insulin, and 18.50 +/- 3.20 (healthy) and 19.08 +/- 3.83 (diabetic) during glargine infusion. The peak epinephrine levels during hypoglycaemia were 767.8 +/- 140.4 pg/ml (regular insulin) and 608.8 +/- 129.9 pg/ml (glargine) among healthy subjects, and 332.5 +/- 54.8 pg/ml (regular insulin) and 321.8 +/- 67.4 pg/ml (glargine) in diabetic patients. Diabetic patients had blunted glucagon responses during hypoglycaemia with either insulin. Both insulins also elicited similar rates of glucose disposal.. We conclude that insulin glargine and regular human insulin elicit comparable symptomatic and counter-regulatory hormonal responses during hypoglycaemia in healthy or diabetic subjects, and induce similar rates of glucose disposal. Since glargine is designed for subcutaneous (s.c.) use, it is possible (though unlikely) that our findings obtained using an intravenous protocol could differ from responses to hypoglycaemia induced by the s.c. route.

Topics: Adult; Blood Glucose; Blood Pressure; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 1; Double-Blind Method; Epinephrine; Female; Glucagon; Glucose Clamp Technique; Heart Rate; Human Growth Hormone; Humans; Hydrocortisone; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Glargine; Insulin, Long-Acting; Male; Norepinephrine; Recombinant Proteins; Reference Values

Metabolic disorders, such as PCOS (polycystic ovarian syndrome) and T2DM (type 2 diabetes mellitus), are associated with menstrual dysfunction, anovulation, infertility, and early pregnancy loss. Ovarian dysfunction is not only related to low pregnancy rates but also to the increased risk of miscarriage. Women with PCOS or T2DM, characterized by hyperinsulinemia, commonly experience ovarian dysfunction. In this study, we first explored whether high insulin levels directly affected ovarian functioning during embryo implantation. Mice in the insulin-treated group were given a subcutaneous injection of human recombinant insulin. After insulin treatment, serum levels of E2 (estrogen), PROG (progesterone), LH (luteinizing hormone), and FSH (follicle-stimulating hormone) were obviously lower, and there was a significant decrement of ovarian GDF9 (growth differentiation factor 9) mRNA. H&E (hematoxylin and eosin) staining showed a greater number of immature follicles and less luteinization in the insulin group. Further autophagy was studied in this process. A significant increase of P62 (SQSTM1/Sequestosome1) and a decrease of Cathepsin B, BECN1 (Beclin 1), and ULK1 (Unc-51-like kinase 1) mRNA in ovary was found in the insulin group. Western blot analysis showed that the expressions of LC3 (microtubule-associated protein 1 light chain 3), BECN1, and Cathepsin B proteins in ovaries from insulin group were obviously reduced, while P62 proteins were significantly increased. All these results illustrated that insulin could directly impair ovarian function during embryo implantation and the imbalance of ovarian autophagy due to insulin. Autophagy could enhance the impaired ovarian function results from insulin.

Topics: Animals; Animals, Outbred Strains; Anovulation; Autophagy; Autophagy-Related Protein-1 Homolog; Beclin-1; Cathepsin B; Disease Models, Animal; Embryo Implantation; Embryo Loss; Female; Gene Expression Regulation, Developmental; Growth Differentiation Factor 9; Hyperinsulinism; Insulin Glargine; Mice; Ovary; Pregnancy; Random Allocation; Sequestosome-1 Protein

Insulin assays are designed to detect endogenous insulin, however, insulin assays produced by different manufacturers may detect exogenous recombinant insulin, with varying degrees of cross-reactivity between different assays. We report a fascinating and difficult case of recurrent hypoglycaemia, where the final diagnosis was established with the help of insulin assays using different platforms.. A 24-year-old female presented with recurrent hypoglycaemic episodes on a background of Type 1 diabetes mellitus and a completely resected synovial sarcoma of the right hip several years previously. She reported significant physical, sexual and emotional abuse leading to reduced appetite and weight loss. Despite withdrawing insulin therapy, she experienced profound hypoglycaemic episodes with detectable C-peptide and inappropriately elevated insulin levels, suggesting endogenous hyperinsulinaemic hypoglycaemia; however, localization studies were negative and finally she was found to have exogenous hyperinsulinaemia after discordant insulin levels were detected using two different insulin assays. The C-peptide level was elevated as a result of stimulation by parenteral dextrose and was suppressed after dextrose was ceased. Her Type 1 diabetes mellitus was fabricated and she had factitious hypoglycaemia.. Factitious hypoglycemia is difficult to diagnose and treat. A low blood glucose level, suppressed C-peptide level and an inappropriately elevated insulin level is the classic finding. We were able to make a diagnosis in the present case after discordant insulin levels were detected on the two different insulin assays, signifying cross-reactivities of the recombinant insulin with the assays. A multidisciplinary team approach with psychiatric input is needed to treat such cases.

Topics: Diabetes Mellitus, Type 1; Diagnosis, Differential; Factitious Disorders; Female; Humans; Hyperinsulinism; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Recurrence; Young Adult

Either endogenous or exogenous hyperinsulinaemia in the setting of insulin resistance promotes phosphorylation and activation of farnesyltransferase, a ubiquitous enzyme that farnesylates Ras proteins. Increased availability of farnesylated Ras at the plasma membrane enhances mitogenic responsiveness of cells to various growth factors, thus contributing to progression of cancer and atherosclerosis. This effect is specific to insulin, but is not related to the type of insulin used. The stimulatory effect of hyperinsulinaemia on farnesyltransferase in the presence of insulin resistance represents one potential mechanism responsible for mitogenicity and atherogenicity of insulin.

Topics: Atherosclerosis; Cell Division; Diabetes Mellitus; Farnesyltranstransferase; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin Resistance; Insulin, Long-Acting; Neoplasms; ras Proteins