Clinical Medicine Insights-Endocrinology and Diabetes最新文献

Cystic fibrosis (CF) is an autosomal recessive chronic condition effecting approximately 70 000 to 100 000 people globally and is caused by a loss-of-function mutation in the CF transmembrane conductance regulator. Through improvements in clinical care, life expectancy in CF has increased considerably associated with rising incidence of secondary complications including CF-related diabetes (CFRD). CFRD is believed to result from β-cell loss as well as insufficient insulin secretion due to β-cell dysfunction, but the underlying pathophysiology is not yet fully understood. Here we review the morphological and cellular changes in addition to the architectural remodelling of the pancreatic exocrine and endocrine compartments in CF and CFRD pancreas. We consider also potential underlying proinflammatory signalling pathways impacting on endocrine and specifically β-cell function, concluding that further research focused on these mechanisms may uncover novel therapeutic targets enabling restoration of normal insulin secretion.

Background: The safe method of instructing insulin dose reduction in combination with SGLT2 inhibitors, dapagliflozin for patients with type 1 diabetes mellitus has not been clarified. In this study, we conducted a stratified, 2-arm, parallel comparative study with the primary endpoint of decreasing the frequency of hypoglycemia by instructing basal insulin dose reduction.

Methods: The study has a multicenter, open-label, 2-arm design; 60 type 1 diabetes mellitus patients are being recruited from 7 hospitals. Study subjects have been stratified into 2 groups based on the ratio of basal insulin daily dose (Basal) to total daily insulin dose (TDD). The subjects whose Basal/TDD ratio is <0.4 are instructed not to reduce Basal but to reduce bolus insulin dose by 10% (group A), and subjects with a Basal/TDD ratio >0.4 will be instructed to reduce Basal by 10% (group B). The primary outcome is the daily frequency of hypoglycemia during the intervention period (SGLT2 inhibitor administration), as determined by self-monitoring of blood glucose. We aimed to confirm a greater reduction in frequency of hypoglycemia in group B (reduced Basal), than in group A (non-reduction of Basal and reduced insulin effect levels by 10%). Baseline hypoglycemia was set at 7 ± 6 times/month. The minimum sample size required to achieve a significance of .05 for a 1-sided t-test with a statistical power at 80% is determined. When the sample size is 26 patients in 1 group, the percentage increase in hypoglycemia exceeds 60%, and the sample size is considered sufficient.

Discussion: In this pilot study, we assumed that, given a sufficient Basal, hypoglycemia would be more frequent in patients with type 1 diabetes when combined with SGLT2 inhibitors, provided the Basal was not reduced.

Xenin bioactivity and its role in normal physiology has been investigated by several research groups since its discovery in 1992. The 25 amino acid peptide hormone is secreted from the same enteroendocrine K-cells as the incretin hormone glucose-dependent insulinotropic polypeptide (GIP), with early studies highlighting the biological significance of xenin in the gastrointestinal tract, along with effects on satiety. Recently there has been more focus directed towards the role of xenin in insulin secretion and potential for diabetes therapies, especially through its ability to potentiate the insulinotropic actions of GIP as well as utilisation in dual/triple acting gut hormone therapeutic approaches. Currently, there is a lack of clinically approved therapies aimed at restoring GIP bioactivity in type 2 diabetes mellitus, thus xenin could hold real promise as a diabetes therapy. The biological actions of xenin, including its ability to augment insulin secretion, induce satiety effects, as well as restoring GIP sensitivity, earmark this peptide as an attractive antidiabetic candidate. This minireview will focus on the multiple biological actions of xenin, together with its proposed mechanism of action and potential benefits for the treatment of metabolic diseases such as diabetes.

Background and aims: Worldwide, type 2 diabetes mellitus accounts for a considerable burden of disease, with an estimated global cost of >800 billion USD annually. For this reason, the search for more effective and efficient therapeutic anti-diabetic agents is continuing. Coumarins are naturally derived and synthetic molecules with a wide variety of biological actions. The most common application of these molecules in medicine is for their thrombostatic activity. This study aims to give an overview of the current knowledge about the applicability of these chemical products in the therapeutic strategy against diabetes and its complications.

Methods: For this purpose, we searched internet databases for publications and abstracts in English that investigated the effects of coumarins or coumarin-like agents with potential anti-diabetic activity.

Results: The result is that a variety of these agents have proven in in vitro, in silico, and simple animal models to possess properties that may reduce the glucose absorption rate in the intestines, increase the level of insulin, increase the cellular uptake of glucose or reduce the gluconeogenesis. In addition, some of these agents also reduced the level of glycation of peptides in diabetic animal models and showed antioxidant properties.

Conclusion: In conclusion, we can summarize that coumarins and their related derivatives may be potential antidiabetic agents. Useful formulations with appropriate pharmacokinetic and pharmacodynamic properties must be developed and tested for their efficacy and toxicity in comprehensive animal models before they can enter clinical trials.

This study examined the feasibility and effect of sedentary behavior (SB) counseling on total sitting time (TST) and glycemic control in people with type 2 diabetes (T2D). Community-dwelling sedentary adults with T2D (n = 10; 8 women; age 65.6 ± 7.31) completed SB counseling (motivational interviewing-informed education about SB) aided by an activity monitor with a vibrotactile feature (activPAL3TM). The monitor was worn for 7 days, on weeks 1 and 13 (without the vibrotactile feature) and during weeks 5 and 9 (with the vibrotactile feature). Intervention feasibility was determined by study retention rates and activity monitor tolerability, and differences between pre- and post-intervention average daily TST. Paired t-test were performed. The effect size (ES) was calculated using Cohen d. All participants attended all study sessions with only 20% reporting moderate issues tolerating the activity monitor. TST time decreased from 11.8 hours ± 1.76 at baseline to 10.29 hours ± 1.84 at 3 months' assessment (P < .05) with a large ES (Cohen d = .88). HbA1c was decreased by 0.51% (P < .05) at the end of the intervention. This study found that the intervention was feasible for sedentary adults with type 2 diabetes.

Background: A frequent comorbidity in cystic fibrosis (CF) is CF related diabetes (CFRD) caused by a gradual decline in insulin secretion. The reduction in the anabolic hormone, insulin, might explain the weight loss that precedes onset of CFRD. We investigated the association between muscle and fat mass in relation to glucose tolerance and insulin function.

Methods: In a cross-sectional study with CF patients (⩾18 years), we conducted an oral glucose tolerance test and dual energy X-ray absorptiometry scan (DXA). Based on plasma glucose, glucose tolerance was defined as normal (NGT): 1-hour <11.1 mmol/L and 2-hour <7.8 mmol/L, impaired (IGT): 2-hour ⩾7.8 and <11.1 mmol/L or CFRD: 2-hour ⩾11.1 mmol/L. Insulin resistance (HOMA-IR) was derived from fasting levels of plasma glucose and plasma insulin, and fat-free and fat mass index (kg/m²) from DXA. Associations were evaluated using linear regression models adjusted for age, sex, and pancreas insufficiency.

Results: Among 79 CF patients with exocrine pancreas insufficiency, impairment of glucose tolerance corresponded to reduced insulin secretion. In the IGT group the fat-free mass index (FFMI) was 1.2 kg/m² (95% CI: [-2.3, -0.03] kg/m², P = .044) lower compared to the NGT group. FFMI increased insignificantly by 0.4 kg/m² (95% CI: [-0.6, 1.5] kg/m², P = .422) among the insulin-treated CFRD group compared to IGT. Fat mass index (FMI) was not different between groups but tended to decrease with glucose tolerance impairment. For each 100 pmol/L increase in fasting insulin FFMI increased by 1.77 kg/m² (95% CI: [0.21, 3.33] kg/m²/pmol/L/100) and FMI increased by 6.15 kg/m² (95% CI: [3.87, 8.44] kg/m²/pmol/L/100). In multivariate analyses, HOMA-IR was positively associated with FFMI (β = 0.5 kg/m²/HOMA-IR, 95% CI: [0.08, 0.92] kg/m²/HOMA-IR, P = .021) and FMI (β = 1.5 kg/m²/HOMA-IR, 95% CI: [0.87, 2.15] kg/m²/HOMA-IR, P < .001).

Conclusions: Muscle mass was significantly lower among participants with impaired glucose tolerance (IGT), while muscle mass was normalized among those treated with insulin.

Background: To evaluate the clinical characteristics, treatment patterns, and clinical effectiveness and safety of high doses of metformin (1500-2500 mg/day) in Indian adults with type 2 diabetes mellitus (T2DM).

Materials and methods: A retrospective, multicentric (n = 241), real-world study included patients with T2DM (aged >18 years) receiving high doses of metformin. Details were retrieved from patient's medical records.

Results: Out of 5695 patients, 62.7% were men with median age was 50.0 years. Hypertension (67.5%) and dyslipidemia (48.7%) were the prevalent comorbidities. Doses of 2000 mg (57.4%) and 1500 mg (29.1%) were the most commonly used doses of metformin and median duration of high-dose metformin therapy was 24.0 months. Metformin twice daily was the most frequently used dosage pattern (94.2%). Up-titration of doses was done in 96.8% of patients. The mean HbA1c levels were significantly decreased post-treatment (mean change: 1.08%; P < .001). The target glycemic control was achieved in 91.2% patients. A total of 83.0% had decreased weight. Adverse events were reported in 156 patients. Physician global evaluation of efficacy and tolerability showed majority of patients on a good to excellent scale (98.2% and 97.7%).

Conclusion: Clinical effectiveness and safety of a high-dose metformin was demonstrated through significant improvement in HbA1c levels and weight reduction.

Cystic fibrosis-related diabetes mellitus (CFRD) is the most common non-pulmonary co-morbidity in cystic fibrosis (CF). CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR), which leads to aberrant luminal fluid secretions in organs such as the lungs and pancreas. How dysfunctional CFTR leads to CFRD is still under debate. Both intrinsic effects of dysfunctional CFTR in hormone secreting cells of the islets and effects of exocrine damage have been proposed. In the current review, we discuss these non-mutually exclusive hypotheses with a special focus on how dysfunctional CFTR in endocrine cells may contribute to an altered glucose homeostasis. We outline the proposed role of CFTR in the molecular pathways of β-cell insulin secretion and α-cell glucagon secretion, and touch upon the importance of the exocrine pancreas and intra-pancreatic crosstalk for proper islet function.

Cushing's syndrome causes increased morbidity and mortality due to cardiovascular and infectious diseases. Exogenous Cushing's syndrome can render the adrenal glands unable to cope with severe infections and may result in Addisonian crisis, which can be fatal if not properly diagnosed and treated. During hospitalization for disease exacerbation, a man on chronic glucocorticoid therapy for Crohn's disease and Cushingoid features developed polymicrobial septic shock together with hypotension that was unresponsive to fluids. On suspicion of relative adrenal insufficiency (cortisol levels were "inadequately" normal), intravenous hydrocortisone was started; norepinephrine was also required to normalize blood pressure. Following clinical improvement, oral cortisone acetate was started. On discharge, he was instructed on how to manage stressful events by increasing oral glucocorticoid treatment or starting a parenteral formulation, if required. Chronic glucocorticoid therapy can cause severe side-effects; in addition, hypoadrenalism can occur in critical illnesses (eg, severe infections). Prompt recognition and proper therapy of this condition can be life-saving.

Background: Stress-induced hyperprolactinemia can be difficult to differentiate from true hyperprolactinema and may result in patients having unnecessary investigations and imaging. We report the results of cannulated prolactin tests with serial prolactin measurements from an indwelling catheter to differentiate true from stress-induced hyperprolactinemia in patients with persistently mildly elevated prolactin levels in both referral and repeat samples.

Methods: Data were collected for 42 patients who had a cannulated prolactin test between January 2017 and May 2018. After cannula insertion, prolactin was measured at 0, 60, and 120 minutes. Normalization is defined as a decline in prolactin to gender-defined normal ranges.

Results: The mean age was 33.8 years (SD ± 9.9), and 37 (88%) were female. Menstrual irregularities were the main presenting symptom in 28.57% of the patients. Prolactin normalized in 12 (28.6%) patients of whom cannulated prolactin test was done. Repeat random prolactin levels were significantly higher in patients whose prolactin did not normalize during the cannulated prolactin test. MRI of the pituitary gland showed an abnormality in 23 out of 28 (82%) patients who did not normalize prolactin, a microadenoma in the majority of patients (18 patients).

Conclusion: The cannulated prolactin test was useful in excluding true hyperprolactinemia in 28.6% of patients with previously confirmed mildly elevated random prolactin on two occasions, thus avoiding over-diagnosis and unnecessary imaging.