Effectiveness of countermeasure for polypharmacy by multidisciplinary team review in patients with diabetes mellitus.

AIMS/INTRODUCTION: Polypharmacy in diabetes patients is related to worse clinical outcomes. The aim of this study was to evaluate the usefulness of our countermeasure for polypharmacy, which combines a pharmacist check followed by a multidisciplinary team review in diabetic patients with polypharmacy. METHODS: A single-center, retrospective observational study was conducted at Gifu University Hospital. Study participants included diabetic patients taking six or more drugs on admission to the diabetes ward between July 2021 and June 2022. Drugs which were discontinued by the present countermeasure were examined, and the number of drugs being taken by each patient was compared between admission and discharge. RESULTS: 102 of 308 patients were taking six or more drugs on admission. The drugs being taken by these patients were evaluated by pharmacists using a checklist for polypharmacy. Eighty-four drugs which were evaluated as inappropriate or potentially inappropriate medications by pharmacists were discontinued following the multidisciplinary team review. The median and mean number of drugs taken by the 102 patients significantly decreased from 9.0 (IQR: 8-12) and 9.26 ± 2.64 on admission to 9.0 (IQR: 6-10) and 8.42 ± 2.95 on discharge (P = 0.0002). We followed up with these patients after discontinuation of the drugs and confirmed that their clinical status had not deteriorated. CONCLUSION: The present countermeasure for polypharmacy, which combines a pharmacist check based on a checklist for evaluating polypharmacy followed by a multidisciplinary team review, was useful for reducing the number of inappropriate or potentially inappropriate medications taken by diabetes patients with polypharmacy.

Association of dipeptidyl peptidase-4 inhibitor use and risk of pancreatic cancer in individuals with diabetes in Japan.

AIMS/INTRODUCTION: This study was designed and carried out to investigate the association of dipeptidyl peptidase-4 inhibitor (DPP-4i) use with pancreatic cancer (PC) in individuals with diabetes in Japan. MATERIALS AND METHODS: The JMDC Claims Database, which contains the medical and prescription information of Japanese employment-based health insurance programs, was used. The primary outcome was duration to the first occurrence of PC (International Classification of Diseases 10th Revision code C25), both all and hospitalized, from prescription of DPP-4is or other oral glucose-lowering agents (GLAs). RESULTS: Individuals with diabetes who received DPP-4is (n = 61,430) or other oral GLAs (n = 83,304) were analyzed. Follow-up periods (median [interquartile range]) were 17 months (8-33) for DPP-4is and 14 months (7-28) for other oral GLAs. Kaplan-Meier curve analysis to determine the duration of first use of DPP4i or other oral GLA to diagnosis of PC disclosed no differences between the two groups in duration to all or hospitalized PC (log-rank test: all, P = 0.7140; hospitalized, P = 0.3446). Cox proportional hazards models showed that use of DPP-4is did not affect the PC risk adjusted for medications, age, sex and risk comorbidities (all, hazard ratio 1.1, 95% confidence interval 0.8-1.3, P = 0.6518; hospitalized, hazard ratio 1.1, 95% confidence interval 0.8-1.4, P = 0.6662). Similar results were obtained when individuals with ≥2 years oral GLA treatment and those with medical checkup data (e.g., smoking or drinking habit) available were analyzed. CONCLUSION: This database study shows that there is not a significant PC risk due to DPP-4i treatment in individuals with diabetes in Japan, but larger studies with longer follow up are required to confirm these findings.

Advances in insulin therapy from discovery to ß-cell replacement.

Insulin therapy using insulin purified from porcine or bovine pancreas revolutionized diabetes therapy in the 1920s. A series of advances including cloning human insulin cDNA enabled the development of recombinant human insulin with improved features. Insulin treatment for diabetes may well be upended by ß-cell replacement therapy in the coming decades.

Semaglutide is effective in type 2 diabetes and obesity with schizophrenia.

Background: Prevention and treatment of type 2 diabetes and obesity are problematic for individuals with schizophrenia partly because atypical antipsychotics and mental distress themselves increase appetite, thus promoting subsequent body weight gain and deterioration of glycemic control. Glucagon-like peptide-1 (GLP-1) receptor agonists have been gaining attention for their glucose-lowering and body weight-reducing effects in obese individuals with type 2 diabetes generally, but their effects in those also having schizophrenia have not been adequately addressed. Case presentation: This case was a 50-year-old obese woman having type 2 diabetes and schizophrenia. Although she was receiving oral anti-diabetes treatment, her HbA1c remained inadequately controlled (8.0-9.0%) partly due her difficulty in following instructions on heathy diet and exercise. In addition, she was repeatedly hospitalized due to suicide attempts by overdosing on her anti-psychotic and anti-diabetes drugs. Her HbA1c was elevated to as high as 10.2% despite the use of multiple anti-diabetes drugs including the GLP-1 receptor agonist dulaglutide, and she was hospitalized in our department. We chose the GLP-1 receptor agonist semaglutide to replace dulaglutide along with a multidisciplinary team approach that included a cognitive-behavioral therapist. The patient perceived that her hunger was suppressed when she started receiving semaglutide 0.5 mg. After discharge, semaglutide was remarkably more effective than dulaglutide in that it reduced and maintained the patient's HbA1c and body weight for 6 months after initiation of the drug. Conclusion: The GLP-1 receptor agonist semaglutide can be effective in maintaining appropriate control of glycemia and body weight in diabetes and obesity with schizophrenia.

A case of familial hypocalciuric hypercalcemia type 1 due to CASR p.Pro55Leu mutation.

BACKGROUND: Familial hypocalciuric hypercalcemia (FHH) is a rare autosomal dominant disease, which requires differential diagnosis from relatively common primary hyperparathyroidism (PHPT) in order to avoid unnecessary surgery. CASE PRESENTATION: A 16-year-old female had been followed by the department of psychosomatic medicine at our institution. Throughout the follow-up period, her plasma calcium levels were high, plasma Pi levels were relatively low, and plasma intact PTH was relatively high. She was referred to our department to determine the cause of her hypercalcemia. Her 24 h urinary calcium excretion was as low as 100 mg/day, and calcium creatinine clearance ratio was below 0.01. Moreover, she had a family history of hypercalcemia (proband, her brother, and her father). The genetic testing for her family revealed that she, her brother, and her father were definitively diagnosed with FHH type 1 due to the heterozygous calcium-sensing receptor mutation (NM_00388:4:c.164C > T:p.Pro55Leu). CONCLUSION: We experienced a 16-year-old female with FHH, in whom genetic testing identified the heterozygous calcium-sensing receptor mutation (NM_00388:4:c.164C > T:p.Pro55Leu) as pathogenic, permitting a definitive diagnosis of FHH type 1. The genetic testing for calcium sensing receptor is beneficial to distinguish asymptomatic primary hyperparathyroidism from FHH.

Graves' Disease after Administration of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccine in a Type 1 Diabetes Patient.

Although there is a great demand for increased coronavirus disease 2019 (COVID-19) vaccination worldwide, rare side effects of the vaccine in susceptible individuals are attracting attention. We recently treated a patient with type 1 diabetes who had HLA-A*240201/A*020101, B*5401/B*5601, DRB1*0405/DRB1*0405, DPB1*0501/DPB1*0501 and DQB1*0401/DQB1*040 and developed Graves' disease soon after the administration of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. While causal relationships between vaccinations and adverse events are difficult to discern due to both confounding and masking factors, our findings suggest that attention to possible adjuvant-related endocrinological diseases in certain individuals receiving SARS-CoV-2 vaccines is appropriate.

Graves' Disease with Thymic Hyperplasia: The Response of the Thyroid Function, Thyrotropin Receptor Autoantibody, and Thymic Size to Thiamazole Treatment.

We treated a 22-year-old woman suffering from Graves' disease and thymic hyperplasia. She was referred to our institution for a close investigation of thyrotoxicosis and thymic mass. Thyroid tests and magnetic resonance imaging resulted in a diagnosis of Graves' disease and thymic hyperplasia. The thyroid function and thyroid-stimulating hormone receptor antibody (TRAb) were normalized one and five months after thiamazole initiation, respectively. The thymic size began to decrease after 1 month and was further decreased after 5 months; it was normalized after 12 months. The correlation between TRAb titers and the thymic size (R2=0.99) suggested that the patient's autoimmunity might have contributed to the thymic hyperplasia.

First Japanese Family With PDX1-MODY (MODY4): A Novel PDX1 Frameshift Mutation, Clinical Characteristics, and Implications.

CONTEXT: The PDX1 gene encodes pancreatic and duodenal homeobox, a critical transcription factor for pancreatic ß-cell differentiation and maintenance of mature ß-cells. Heterozygous loss-of-function mutations cause PDX1-MODY (MODY4). CASE DESCRIPTION: Our patient is an 18-year-old lean man who developed diabetes at 16 years of age. Given his early-onset age and leanness, we performed genetic testing. Targeted next-generation sequencing and subsequent Sanger sequencing detected a novel heterozygous frameshift mutation (NM_00209.4:c.218delT. NP_000200.1: p.Leu73Profs*50) in the PDX1 transactivation domain that resulted in loss-of-function and was validated by an in vitro functional study. The proband and his 56-year-old father, who had the same mutation, both showed markedly reduced insulin and gastric inhibitory polypeptide (GIP) secretion compared with the dizygotic twin sister, who was negative for the mutation and had normal glucose tolerance. The proband responded well to sitagliptin, suggesting its utility as a treatment option. Notably, the proband and his father showed intriguing phenotypic differences: the proband had been lean for his entire life but developed early-onset diabetes requiring an antihyperglycemic agent. In contrast, his father was overweight, developed diabetes much later in life, and did not require medication, suggesting the oligogenic nature of PDX1-MODY. A review of all reported cases of PDX1-MODY also showed heterogeneous phenotypes regarding onset age, obesity, and treatment, even in the presence of the same mutation. CONCLUSIONS: We identified the first Japanese family with PDX1-MODY. The similarities and differences found among the cases highlight the wide phenotypic spectrum of PDX1-MODY.

Hypoglycemic coma in an elderly adult switched from twice-daily vildagliptin to once-daily glimepiride to improve drug adherence.

BACKGROUND: Elderly adults with diabetes are at increased risk of severe hypoglycemia and hypoglycemic coma due to various conditions including decline in cognitive function, reduced activity of daily living (ADL) and reduced renal function; special cautions are, therefore, recommended to avoid these life-threatening events. CASE PRESENTATION: A 92-year-old female was admitted to our institution because of severe coma. Upon arrival, her serum C-peptide was 1.64 ng/mL despite low plasma glucose (24 mg/dL) and serum glimepiride (40.85 ng/mL). She had past history of compression fracture of her lumbar spine, which substantially affected her ADL. Her score on the dementia assessment sheet for community-based integrated care system-8 items (DASC-8) was 26 points. She had been receiving 12 oral medications for diabetes, essential hypertension, chronic gastritis and constipation from her nearby clinic. Her physician-in-charge had found that she was not taking her medications properly and simplified her prescription regimen to 3 oral medications with vildagliptin 50 mg twice daily replaced by glimepiride 3 mg once daily and asked her son to assist in taking the drugs 6 days before her admission to our hospital. While her consciousness level was improved to some extent, she was transferred to a long-term care bed hospital because it had become too difficult to care for her at home. CONCLUSIONS: It is important to note that anti-diabetes drugs should be carefully selected based on each patient's cognitive function and ADL, and that the reasoning should be shared with the general practitioners involved to avoid severe hypoglycemic events. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-021-00510-9.

Glucokinase-maturity onset diabetes mellitus in the young suggested by factory-calibrated glucose monitoring data: a case report.

Glucokinase has an important role in regulating glycolysis as a glucose sensor in liver and pancreatic ß cells. Glucokinase-maturity onset diabetes in young (GCK-MODY also known as MODY2) is caused by autosomal dominant gene mutation of the GCK gene; it is characterized by mild fasting hyperglycemia and small 2-h glucose increment during 75 g-oral glucose tolerance test (OGTT) as well as near-normal postprandial glucose variabilities. A 10-year-old girl with family history of diabetes visited her physician after being found positive for urinary glucose by school medical checkup. She received a diagnosis of diabetes based on the laboratory data: 75 g-OGTT (mild fasting hyperglycemia and small 2-h glucose increment) and factory-calibrated glucose monitoring (mild elevation of average glucose level and near-normal glycemic variability), which raised suspicion of GCK-MODY. She was then referred to our institution for genetic examination, which revealed a GCK heterozygous mutation (NM_000162: exon10: c.1324G>T: p.E442X) in the proband as well as in her mother and maternal grandmother, who had been receiving anti-diabetes medications without knowing that they had GCK-MODY specifically. GCK-MODY cases show incidence of microvascular and macrovascular diseases similar to that of normal subjects, and their glucose levels are adequately controlled without anti-diabetes drug use. Thus, early and definitive diagnosis of MODY2 by genetic testing is important to avoid unnecessary medication.

Effects of physician's diabetes self-management education using Japan Association of Diabetes Education and Care Diabetes Education Card System Program and a self-monitoring of blood glucose readings analyzer in individuals with type 2 diabetes: An exploratory, open-labeled, prospective randomized clinical trial.

AIMS/INTRODUCTION: This 6-month, single-center, prospective, open-labeled, randomized trial was designed to investigate whether physicians' diabetes self-management education using an education tool developed by the Japan Association of Diabetes Education and Care and a self-monitoring of blood glucose (SMBG) analyzer improves glycemic control in individuals with type 2 diabetes receiving insulin and SMBG. MATERIALS AND METHODS: Participants were randomized into intervention (I) and control (C) groups. Both groups received physicians' diabetes self-management education at each hospital visit, whereas the Japan Association of Diabetes Education and Care education tool and the SMBG readings analyzer was used in group I, but not group C. All participants filled out a diabetes treatment-related quality of life form and an original questionnaire on SMBG use with five questions (Q1-Q5) before and after the study period. RESULTS: A total of 76 individuals were recruited and randomized. Glycated hemoglobin (HbA1c) was significantly improved during the study period in group I, whereas no significant change was observed in group C. The change in HbA1c was greater in group I, although it did not reach statistical significance. The diabetes treatment-related quality of life total score was not changed in either group. Interestingly, the score of Q1 ("How important is SMBG to you?") in the SMBG questionnaire was unchanged in group I, whereas it was significantly decreased in group C. HbA1c change was independently associated with changes in insulin dose and SMBG Q1 score. CONCLUSION: Greater HbA1c-lowering by physicians' diabetes self-management education using the Japan Association of Diabetes Education and Care education tool and SMBG analyzer in individuals with type 2 diabetes receiving insulin and SMBG was suggested, but not confirmed.

Effects of glucagon-like peptide-1 receptor agonists on secretions of insulin and glucagon and gastric emptying in Japanese individuals with type 2 diabetes: A prospective, observational study.

AIMS/INTRODUCTION: Differences in the glucose-lowering mechanisms of glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been noted. Clarifying these differences could facilitate the choice of optimal drugs for individuals with type 2 diabetes and requires investigation in a clinical setting. MATERIALS AND METHODS: A single-arm, prospective, observational study was conducted to evaluate the effects of various GLP-1RAs on postprandial glucose excursion, secretions of insulin and glucagon as well as on the gastric emptying rate. Participants were subjected to meal tolerance tests before and 2 weeks and 12 weeks after GLP-1RA initiation. Effects on postprandial secretions of glucose-dependent insulinotropic polypeptide (GIP) and apolipoprotein B48 were also investigated. RESULTS: Eighteen subjects with type 2 diabetes received one of three GLP-1RAs, i.e., lixisenatide, n = 7; liraglutide, n = 6; or dulaglutide, n = 5. While 12-week administration of all of the GLP-1RAs significantly reduced HbA1c, only lixisenatide and liraglutide, but not dulaglutide, significantly reduced body weight. Postprandial glucose elevation was improved by all of the GLP-1RAs. Postprandial insulin levels were suppressed by lixisenatide, while insulin levels were enhanced by liraglutide. Postprandial glucagon levels were suppressed by lixisenatide. The gastric emptying rate was significantly delayed by lixisenatide, while liraglutide and dulaglutide had limited effects on gastric emptying. GIP secretion was suppressed by lixisenatide and liraglutide. Apolipoprotein B48 secretion was suppressed by all of the GLP-1RAs. CONCLUSIONS: All of the GLP-1RAs were found to improve HbA1c in a 12-week prospective observational study in Japanese individuals with type 2 diabetes. However, differences in the mechanisms of the glucose-lowering effects and body weight reduction were observed.

Elevation of Fasting GLP-1 Levels in Child and Adolescent Obesity: Friend or Foe?

Glucagon-like peptide-1 (GLP-1) receptor agonists have been gaining much attention as a therapeutic approach to type 2 diabetes and obesity. Stinson et al recently reported that fasting GLP-1 is higher in children and adolescents with overweight/obesity and that it associates with cardiometabolic risk factors in a cross-sectional study comprising more than 4000 subjects. Obvious questions include why fasting GLP-1 is significantly increased in children and adolescents with overweight/obesity and why this is correlated with cardiometabolic risks. It has been shown that the inflammatory cytokine interleukin-6 (IL-6) stimulates GLP-1 secretion from pancreatic α-cells. IL-6-induced GLP-1 secretion could therefore play a role in expanding the ß-cell reservoir in compensation for increased insulin needs due to exacerbation of insulin resistance. On the other hand, augmented GLP-1 secretion leads to increased insulin secretion, thereby enhancing hepatic lipogenesis and stimulating adipogenesis, which might underlie the associations of fasting GLP-1 with % body fat, triglycerides, and alanine aminotransferase. It is also possible that GLP-1 levels are naturally increased to oppose body weight gain to maintain body weight. However, it is important to note the differing biological effects of GLP-1 at physiological and pharmacological levels, which are evident in body weight reduction by GLP-1 receptor agonists and DPP-4 inhibitors. The Stinson study clearly demonstrated that fasting GLP-1 associates with overweight/obesity and cardiometabolic risk factors in children and adolescents. However, additional experiments need to be carried out to fully understand the relevance of these observations to human disease and health.

A novel RFX6 heterozygous mutation (p.R652X) in maturity-onset diabetes mellitus: A case report.

Heterozygous RFX6 mutation has emerged as a potential cause of maturity-onset diabetes mellitus of the young (MODY). A 16-year-old female was diagnosed with diabetes by her family doctor and was referred to our institution for genetic examination. Genetic testing revealed a novel RFX6 heterozygous mutation (NM_173560: exon17: c.1954C>T: p.R652X) in the patient and in her mother and brother. She had no islet-specific autoantibodies and showed a reduced meal-induced response of insulin, glucose-dependent insulinotropic polypeptide, and glucagon-like peptide-1, which is consistent with the phenotype of MODY due to heterozygous RFX6 mutation. In conclusion, we report a case of MODY due to a novel heterozygous mutation, p.R652X.

Effects of ChREBP deficiency on adrenal lipogenesis and steroidogenesis.

Carbohydrate response element-binding protein (ChREBP) is critical in the regulation of fatty acid and triglyceride synthesis in the liver. Interestingly, Chrebp-/- mice show reduced levels of plasma cholesterol, which is critical for steroid hormone synthesis in adrenal glands. Furthermore, Chrebp mRNA expression was previously reported in human adrenal glands. Thus, it remains to be investigated whether ChREBP plays a role directly or indirectly in steroid hormone synthesis and release in adrenal glands. In the present study, we find that Chrebp mRNA is expressed in mouse adrenal glands and that ChREBP binds to carbohydrate response elements. Histological analysis of Chrebp-/- mice shows no adrenal hyperplasia and less oil red O staining compared with that in WT mice. In adrenal glands of Chrebp-/- mice, expression of Fasn and Scd1, two enzymes critical for fatty acid synthesis, was substantially lower and triglyceride content was reduced. Expression of Srebf2, a key transcription factor controlling synthesis and uptake of cholesterol and the target genes, was upregulated, while cholesterol content was not significantly altered in the adrenal glands of Chrebp-/- mice. Adrenal corticosterone content and plasma adrenocorticotropic hormone and corticosterone levels were not significantly altered in Chrebp-/- mice. Consistently, expression of genes related to steroid hormone synthesis was not altered. Corticosterone secretion in response to two different stimuli, namely 24-h starvation and cosyntropin administration, was also not altered in Chrebp-/- mice. Taking these results together, corticosterone synthesis and release were not affected in Chrebp-/- mice despite reduced plasma cholesterol levels.

A Review of Recent Findings on Meal Sequence: An Attractive Dietary Approach to Prevention and Management of Type 2 Diabetes.

While adjustment of total energy and nutritional balance is critically important, meal sequence, a relatively simple method of correcting postprandial hyperglycemia, is becoming established as a practical dietary approach for prevention and management of diabetes and obesity. Meal sequence, i.e., consumption of protein and/or fat before carbohydrate, promotes secretion of glucagon-like peptide-1 (GLP-1) from the gut and ameliorates secretions of insulin and glucagon and delays gastric emptying, thereby improving postprandial glucose excursion. GLP-1 is known to suppress appetite by acting on the hypothalamus via the afferent vagus nerve. Thus, enhancement of GLP-1 secretion by meal sequence is expected to reduce body weight. Importantly, consumption of a diet rich in saturated fatty acids such as meat dishes before carbohydrate increases secretions of not only GLP-1 but also glucose-dependent insulinotropic polypeptide (GIP), which promotes energy storage in adipose tissue and may lead to weight gain in the long term. Dietary fiber intake before carbohydrate intake significantly reduces postprandial glucose elevation and may have a weight loss effect, but this dietary strategy does not enhance the secretion of GLP-1. Thus, it is suggested that their combination may have additive effects on postprandial glucose excursion and body weight. Indeed, results of some clinical research supports the idea that ingesting dietary fiber together with meal sequence of protein and/or fat before carbohydrate benefits metabolic conditions of individuals with diabetes and obesity.

Cardioprotective effects of GLP-1(28-36a): A degraded metabolite or GLP-1's better half?

Molecular mechanism underlying glucagon-like peptide-1 exertion of cardioprotective effects in glucagon-like peptide-1 receptor-dependent and -independent manners. Glucagon-like peptide-1 (28-36a) enters coronary artery endothelial cells through macropinocytosis and binds to mitochondrial trifunctional protein-α, shifting substrate utilization to increase adenosine triphosphate production and modulating a adenosine triphosphate-sensor soluble adenylyl cyclase, thereby producing cyclic adenosine monophosphate and activating protein kinase A to exert cytoprotection from oxidative injury.