Amylin, Another Important Neuroendocrine Hormone for the Treatment of Diabesity.

Diabetes mellitus is a devastating chronic metabolic disease. Since the majority of type 2 diabetes mellitus patients are overweight or obese, a novel term-diabesity-has emerged. The gut-brain axis plays a critical function in maintaining glucose and energy homeostasis and involves a variety of peptides. Amylin is a neuroendocrine anorexigenic polypeptide hormone, which is co-secreted with insulin from ß-cells of the pancreas in response to food consumption. Aside from its effect on glucose homeostasis, amylin inhibits homeostatic and hedonic feeding, induces satiety, and decreases body weight. In this narrative review, we summarized the current evidence and ongoing studies on the mechanism of action, clinical pharmacology, and applications of amylin and its analogs, pramlintide and cagrilintide, in the field of diabetology, endocrinology, and metabolism disorders, such as obesity.

The SAGE study: Global observational analysis of glycaemic control, hypoglycaemia and diabetes management in T1DM.

AIMS: To describe glycaemic control and diabetes management in adults with type 1 diabetes (T1DM), in a real-life global setting. MATERIALS AND METHODS: Study of Adults' GlycEmia (SAGE) was a multinational, multicentre, single visit, noninterventional, cross-sectional study in adult patients with T1DM. Data were collected at a single visit, analysed according to predefined age groups (26-44, 45-64 and ≥65 years) and reported across different regions. The primary endpoint was the proportion of participants achieving HbA1c  less than 7.0 % in each age group. Secondary endpoints included incidence of hypoglycaemia, severe hypoglycaemia and severe hyperglycaemia leading to diabetic ketoacidosis (DKA) and therapeutic management of T1DM. RESULTS: Of 3903 included participants, 3858 (98.8%) were eligible for the study. Overall, 24.3% (95% confidence interval [CI]: 22.9-25.6) of participants achieved the glycaemic target of HbA1c  less than 7.0 %, with more participants achieving this target in the 26-44 years group (27.6% [95% CI: 25.5-29.8]). Target achievement was highest in Eastern and Western Europe, and lowest in the Middle East. The incidence of hypoglycaemia and of severe hyperglycaemia leading to DKA tended to decrease with age, and varied across regions. Age and regional differences were observed in therapeutic management, including types of device/insulin usage, frequency of insulin dose adjustment and technology usage. CONCLUSIONS: Glycaemic control remains poor in adults with T1DM globally. Several areas of treatment may be optimised to improve outcomes, including supporting patient self-management of insulin therapy, increasing use of technologies such as CGM, and greater provision of healthcare support.

Patient-reported outcomes in adults with type 1 diabetes in global real-world clinical practice: The SAGE study.

AIMS: To conduct a secondary analysis of the SAGE study to evaluate the association between glycaemic control and patient-reported outcomes (PROs), in adults with type 1 diabetes (T1DM) across different age groups and regions. MATERIALS AND METHODS: SAGE was a multinational, cross-sectional, observational study in adults with T1DM. Data were collected at a single visit, analysed according to predefined age groups (26-44, 45-64, and ≥65 years), and reported across different regions. PRO questionnaires were applied to assess hypoglycaemia fear (Hypoglycemia Fear Survey-II), diabetes-related distress (Problem Areas In Diabetes questionnaire), insulin treatment satisfaction (Insulin Treatment Satisfaction Questionnaire), and diabetes-specific quality of life (QoL; Audit of Diabetes-Dependent Quality of Life). Multivariable analysis was performed to evaluate the relationship between glycated haemoglobin (HbA1c) target achievement (<7% and individualised targets) with PRO scores. RESULTS: The PRO scores showed relatively low levels of diabetes-related emotional distress and fear of hypoglycaemia, moderate to high treatment satisfaction, and low diabetes-related impact on QoL. Results were generally comparable across age groups with some regional variability. Achievement of the HbA1c <7% target was associated with less worry about hypoglycaemia, lower diabetes-related emotional distress, higher insulin treatment satisfaction, and higher QoL. Achievement of individualised HbA1c targets was associated with lower diabetes-related emotional distress and higher insulin treatment satisfaction. CONCLUSIONS: Better glycaemic control was most closely associated with low emotional distress due to diabetes and high patient-reported insulin treatment satisfaction.

Are the cardiovascular and kidney benefits of empagliflozin influenced by baseline glucose-lowering therapy?

AIMS: In the EMPA-REG OUTCOME® trial, the sodium-glucose cotransporter 2 inhibitor empagliflozin when given in addition to standard care improved cardiovascular (CV) and renal outcomes, and reduced mortality. Trial participants were on a variety of glucose-lowering therapies at baseline, some of which could potentially affect CV risk. This analysis investigated whether the use of background diabetes therapy affected the risk of CV death, hospitalizations for heart failure, and progression of chronic kidney disease, among patients treated with empagliflozin. MATERIALS AND METHODS: Patients meeting inclusion and exclusion criteria were randomized to placebo, empagliflozin 10 mg or empagliflozin 25 mg; glucose-lowering therapy was to remain unchanged for 12 weeks and then adjusted to achieve glycaemic control according to local guidelines. Differences in risk of cardio-renal outcomes between empagliflozin and placebo by baseline use of metformin, sulphonylurea (SU) and insulin were assessed using a Cox proportional hazards model. RESULTS: Of 7020 eligible patients, 74% were receiving metformin, 43% SU and 48% insulin at baseline (each alone or in combination); the most common regimens were metformin plus SU (20%) and metformin plus insulin (20%). Empagliflozin reduced the risk of CV death irrespective of the use of: metformin [with: hazard ratio (HR) 0.71 (95% confidence interval, CI, 0.54-0.94); without: 0.46 (0.32-0.68); Pinteraction = 0.07]; SU [with: HR 0.64 (0.44-0.92); without: 0.61 (0.46-0.81); Pinteraction = 0.85]; or insulin [with: HR 0.63 (0.46-0.85); without: 0.61 (0.44-0.85); Pinteraction = 0.92]. Reductions in three-point major adverse CV events, hospitalizations for heart failure, and all-cause mortality were consistent across subgroups of baseline therapies. Empagliflozin reduced the risks of incident or worsening nephropathy versus placebo irrespective of the use of SU or insulin at baseline (Pinteraction > 0.05), but there was a greater reduction in this risk for patients not using metformin [HR 0.47 (95% CI 0.37-0.59)] versus those using metformin [HR 0.68 (95% CI 0.58-0.79)] at baseline (Pinteraction = 0.01). CONCLUSIONS: The addition of empagliflozin to antihyperglycaemic regimens of patients with type 2 diabetes and CV disease consistently reduced their risks of adverse CV outcomes and mortality irrespective of baseline use of metformin, SU or insulin. For chronic kidney disease progression, there may be a larger benefit from empagliflozin in those patients who are not using metformin.

The Importance of Acromegaloid Physical Features for Clinical Practice.

Acromegaly and gigantism are hormonal disorders which develop as a consequence of chronic growth hormone hypersecretion. The prefix pseudo- is used to describe a certain clinical condition without a clearly proven characteristic of pathophysiological mechanism and basic biochemical features; pseudoacromegaly or acromegaloidism match the definition from above. In this case reports, we will try to provide a concise overview of diagnostic evaluation of acromegaloid physical appearance, while discussing two cases of patients who have similar clinical acromegaloid features as the first sign of the disease but have completely different etiologic backgrounds of their acromegalic appearance. The first case is of a 57-year-old male who presented with a marked acral growth and coarse facial features, but the diagnosis of secondary amyloidosis caused by multiple myeloma was confirmed just after biopsy of tongue and buccal mucosa. The second case is that of a 63-year-old male with an acromegaloid appearance caused by ectopic secretion of GH secreting lung carcinoma. The early diagnosis of ectopic acromegaly and pseudoacromegaly is still a challenging process. The key task is to confirm the GH axis abnormalities and establish the underlying disease, as a crucial step for faster treatment and need to avoid unnecessary therapeutic procedures to decreased mortality and improved quality of life.

Glycemic Variability in Type 1 Diabetes Mellitus Pregnancies-Novel Parameters in Predicting Large-for-Gestational-Age Neonates: A Prospective Cohort Study.

Pregnancies with type 1 diabetes mellitus (T1DM) have a high incidence of large-for-gestational-age neonates (LGA) despite optimal glycemic control. In recent years, glycemic variability (GV) has emerged as a possible risk factor for LGA, but the results of the conducted studies are unclear. This study analyzed the association between GV and LGA development in pregnancies with T1DM. This was a prospective cohort study of patients with T1DM who used continuous glucose monitoring (CGM) during pregnancy. Patients were followed from the first trimester to birth. GV parameters were calculated for every trimester using the EasyGV calculator. The main outcomes were LGA or no-LGA. Logistic regression analysis was used to assess the association between GV parameters and LGA. In total, 66 patients were included. The incidence of LGA was 36%. The analysis extracted several GV parameters that were significantly associated with the risk of LGA. The J-index was the only significant parameter in every trimester of pregnancy (odds ratios with confidence intervals were 1.33 (1.02, 1.73), 3.18 (1.12, 9.07), and 1.37 (1.03, 1.82), respectively. Increased GV is a risk factor for development of LGA. The J-index is a possible novel GV parameter that may be assessed in all three trimesters of pregnancy together with glycated hemoglobin and time-in-range.

The prevalence of depression and anxiety in seafarers type 2 diabetic patients.

Depression and anxiety are co-morbid condition in diabetes as disease-related psychological reactions on this chronic metabolic illness. This study was aimed to determine the occurrence of depression and anxiety in seafarer's type 2 diabetic patients. A random sample of 52 diabetic seafarers treated with diet and oral glucose lowering agents, and 56 healthy seafarers were screened for depression with The Beck Depression Inventory (BDI) and for anxiety with State-Trait Anxiety Inventory (STAI 1, STAI 2). Depression (BDI > 18.5) and anxiety (STAI < 28.5) was significantly higher in the group of diabetic seafarers than in control group (more than 30%). Significant correlation was noted between depression and duration of diabetes mellitus, degree of obesity and poor glycaemic control (HbA1C > 8%) and longer duration of shipping routes (over 6 months). The proportion of depression and anxiety was found higher in seafarer's type 2 diabetic patients than in the healthy seafarers.

How activity of inflammatory bowel disease influences bone loss.

Bone loss is a common problem for individuals with inflammatory bowel disease (IBD). The aim of our study was to assess bone mineral density (BMD) in patients with IBD and to investigate the role of corticosteroid (CS) use and duration and activity of disease on BMD. Ninety-two patients (56 men and 36 women) with IBD, of whom 32 had ulcerative colitis (UC) and 60 had Crohn's disease (CD), underwent clinical assessment. Lumbar and femoral neck BMDs were measured by dual-energy X-ray absorptiometry. Osteopenia was observed in 14 patients (43%) with UC and in 24 patients (40%) with CD (p=0.187). Four patients (12%) with UC and 7 patients (11%) with CD had osteoporosis (p=0.308). Femoral BMD decreased in patients with long duration of CS use and correlated inversely with disease activity. Multiple regression analysis of BMD showed that statistically significant risk factors were duration of active disease and body mass index as well. Based on our results, it is necessary to take into account the risk of decreased BMD in patients with IBD. It is most important to achieve disease remission as soon as possible in addition to nutritional support.

Pregnancy in Patients with Type One Diabetes Mellitus Treated with Continuous Subcutaneous Insulin Infusion-Preconception Basal Insulin Dose as a Potential Risk Factor for Fetal Overgrowth?

Despite widespread use of technology, type one diabetes mellitus (T1DM) is still a great clinical challenge during pregnancy. This study aims to assess how prenatal variables of T1DM patients using continuous subcutaneous insulin infusion (CSII) influence pregnancy outcomes. We performed a retrospective study of 35 patients with T1DM treated with CSII during pregnancy. Alterable preconception variables (A1C, body mass index, basal and bolus insulin dose) were analysed as possible contributors to birth weight and large-for-gestational-age (LGA) prevalence. Inclusion criteria were presence of T1DM for more than two years, A1C < 7.4% and treatment with CSII for at least three months prior to conception. The preconception basal insulin dose and A1C had a significant correlation to the neonatal birth weight (p = 0.01, r = 0.4 and p = 0.04, r = 0.3, respectively) and were significant in regression analysis together contributing 22% of the variance in birth weight percentiles (sig = 0.17, R square = 0.22). Prevalence of LGA was 46%. Women who had LGA neonates also had a higher preconception basal insulin dose compared to women with non-LGA neonates (26 ± 9 vs. 18 ± 7 IU (international units), p = 0.01). The LGA group had a higher preconception A1C, but it did not reach statistical significance (6.5 ± 0.5% vs. 6.2 ± 0.9%, respectively, p = 0.2). Women with T1DM treated with CSII who had unregulated glycaemia and more basal insulin were at greater risk for development of LGA neonates.

The effects of long-term experimental diabetes mellitus type I on skeletal muscle regeneration capacity.

Muscle fibers are dynamic structures capable of altering their phenotype under various pathological conditions. The aim of the present study was to investigate the influence of long-lasting diabetes mellitus on the process of muscle regeneration in the skeletal muscle. Wistar rats were made diabetic by a single intraperitoneal injection of streptozotocin (STZ). The regeneration process in the skeletal muscle was induced in slow (m. soleus, SOL) and fast (m. extensor digitorum longus, EDL) muscles by injection of local anesthetic (bupivacaine). Skeletal muscles were analyzed 10 days, 4 and 8 weeks after bupivacaine treatment. Diabetes mellitus has changed morphological properties of both slow and fast skeletal muscles during the process of regeneration. These changes are evident in redistribution of muscle fibers and significant level of atrophy. All fiber types of diabetic fast muscles showed stronger atrophy than muscle fibers in slow muscles which have more oxidative metabolism. The changes of redistribution of muscle fibers depend on duration of diabetes and affect all types of muscle fibers.

CARMELINA: An important piece of the DPP-4 inhibitor CVOT puzzle.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of glucose-lowering agent for type 2 diabetes (T2D) that are commonly used in clinical practice. With the recent disclosure of data from the CARMELINA cardiovascular outcomes trial (CVOT), which investigated linagliptin, CV and renal outcomes data are now available for four agents in the DPP-4 inhibitor class that are approved in most markets. To consider how the CARMELINA study may be interpreted, and the relevance for our clinical practice, we convened as an expert group of diabetes specialists from the Central and Eastern Europe region to discuss the new disclosures. Our discussions revealed a general confidence in safety across the class that is further supported by CARMELINA. However, we also concluded that there are important differences in the available evidence level between agents in the setting of heart failure and data on renal outcomes. Here, we noted the clinical relevance to our practice of the study population in CARMELINA, which is unique among CVOTs in including a majority of patients with chronic kidney disease (CKD). Given the risk for future development of renal impairment that is associated with T2D even in patients without current overt CKD, we believe that the CARMELINA study provides important new insights that are clinically relevant for a broad range of patients. Finally, we discuss how these insights can be integrated into the approach to the pharmacotherapeutic management of hyperglycaemia that is recommended in newly updated guidelines.

Reg IV protein is expressed in normal rat tissue.

The Reg IV gene has been documented in the colon, small intestine, stomach and pancreas of the human. Expression of the Reg IV in different cell types has been associated with regeneration, cell growth and cell survival, cell adhesion and resistance to apoptosis. It is unknown whether the Reg IV protein is present in the normal rat tissue. The aim of this study was to reveal the expression of the Reg IV protein in the rat spleen and colon. Western blot analysis using antibody specific for Reg IV protein were performed on rat spleen and colon extracts. Low level of Reg IV expression was found in all examined colon samples. The expression of Reg IV protein in spleen tissue was significantly higher than in the colon. Reg IV protein was immunohistochemically stained in a few epithelial cells in the basal portion of colon crypts and in a large spleen cells which were scattered in the red pulp. Our results demonstrate for the first time the presence of the Reg IV protein expression in the healthy spleen and colon tissue of the rat. Other members of the Reg family, Reg I and Reg III proteins have been shown to act as a growth factors in gastrointestinal tract, but without further experiments we can only assume the potential role of the Reg IV protein in spleen and colon cell growth.

Inverse Levels of Adiponectin in Type 1 and Type 2 Diabetes Are in Accordance with the State of Albuminuria.

Aims. To investigate the behaviour of adiponectin (ApN) in patients with type 1 and type 2 diabetic nephropathy. Methods. ApN and inflammatory and other markers of the metabolic syndrome were compared across diabetes types, albumin excretion rate (AER), and creatinine clearance (CrCl) categories in 219 type 1 and type 2 diabetic patients. Results. Significant differences among ApN levels according to AER were found in both types of diabetes (F = 8.45, df = 2, P < 0.001). With the progression of albuminuria, ApN increased in type 1 and decreased in type 2 diabetes. Patients with decreased CrCl had higher ApN levels than those with normal CrCl in either type of diabetes (F = 12.7, df = 1, P < 0.001). The best model for ApN (R (2) = 0.9002) obtained from stepwise regression in type 1 diabetes included CrCl, BMI, WBC, CRP, and age, while in type 2 diabetes (R (2) = 0.2882) it included ppPG, LDL, and UA. Conclusion. ApN behaved differently in relation to albuminuria, increasing with its progression in type 1 diabetes and decreasing in type 2 diabetes. It was however increased in the subgroups with decreased CrCl in both types of diabetes. Albuminuria seems to be more important than renal insufficiency in the definition of ApN levels in type 1 and type 2 diabetes.

Reg IV protein and mRNA expression in different rat organs.

The Reg IV gene has been documented in the human colon, small intestine, stomach and pancreas. Expression of the Reg IV in different cell types has been associated with regeneration, cell growth and cell survival, cell adhesion and resistance to apoptosis. Since the distribution of the Reg IV protein in normal rat tissues is unknown, the aim of this study was to reveal the expression of the Reg IV protein in structurally and functionally different rat organs. The expression of Reg IV gene was analyzed by Western blot and reverse transcription-polymerase chain reaction. Immunohistochemistry was used to localize Reg IV protein. Reg IV protein was expressed in pancreas, stomach, small intestine, colon, brain, spleen, kidney and urinary bladder in two-month-old male Wistar rats. In addition, the expression of Reg IV mRNA by reverse transcription-polymerase chain reaction was confirmed. Our study provides detailed information about the expression and localization of Reg IV protein in different rat organs. These findings provide an evidence of Reg IV expression in different rat organs, which may help elucidate a potential role in growth and proliferation of different cells like other members of the Reg family genes which act as growth factors in the different organs.