Mathematical Models of the Effect of Glucagon on Glycemia in Individuals With Type 2 Diabetes Treated With Dapagliflozin.

Context: Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels by promoting urinary glucose excretion, but their overall effects on hormonal and metabolic status remain unclear. Objective: We here investigated the roles of insulin and glucagon in the regulation of glycemia in individuals treated with an SGLT2 inhibitor using mathematical model analysis. Methods: Hyperinsulinemic-euglycemic clamp and oral glucose tolerance tests were performed in 68 individuals with type 2 diabetes treated with the SGLT2 inhibitor dapagliflozin. Data previously obtained from such tests in 120 subjects with various levels of glucose tolerance and not treated with an SGLT2 inhibitor were examined as a control. Mathematical models of the feedback loops connecting glucose and insulin (GI model) or glucose, insulin, and glucagon (GIG model) were generated. Results: Analysis with the GI model revealed that the disposition index/clearance, which is defined as the product of insulin sensitivity and insulin secretion divided by the square of insulin clearance and represents the glucose-handling ability of insulin, was significantly correlated with glycemia in subjects not taking an SGLT2 inhibitor but not in those taking dapagliflozin. Analysis with the GIG model revealed that a metric defined as the product of glucagon sensitivity and glucagon secretion divided by glucagon clearance (designated production index/clearance) was significantly correlated with blood glucose level in subjects treated with dapagliflozin. Conclusion: Treatment with an SGLT2 inhibitor alters the relation between insulin effect and blood glucose concentration, and glucagon effect may account for variation in glycemia among individuals treated with such drugs.

Synthesis of Tricyclic Fused 6-5-4 Carbocycles via Acid-Promoted Cascade Intramolecular Cyclization of Allenylsilane-Tethered Cyclohexadienones.

The reaction of 2,5-cyclohexadienones with methylene-tethered allenylsilane in the presence of Lewis or Brønsted acids leads to a cascade of intramolecular cyclization, yielding stereoselective tricyclic fused 6-5-4 carbocycles featuring a silyl-methylenecyclobutane ring. This transformation is notable for the diastereoselective asymmetric desymmetrization of prochiral dienones, attributed to the axial chirality of allene.

Amyloid deposition through endocytosis in vascular endothelial cells.

No mechanistic lead is known for establishing AL amyloid deposits in organs. We here report an electron microscopic (EM) analysis in a case of intestinal AL amyloidosis before initiating treatment for amyloidosis. The dense deposits of amyloid fibrils are concentrated around the small blood vessels in the submucosal area of intestinal tissue. Surprisingly, we observed endothelial cells (ECs) of blood vessels containing plenty of endocytotic (pinocytotic) and transcytotic vesicles at the luminal side and above the basement membrane, indicating the one-way active trafficking of either the immunoglobulin (Ig) light chain or preassembled amyloid fibrils from the luminal side of ECs to the extraluminal area of ECs. Immunoelectron microscopy displayed that the immuno-gold signals were observed in the vascular cavity and the subendothelial area of amyloid deposits. However, there is no sign of an Ig light chain in pinocytotic vesicles. Therefore, the intestinal ECs may actively pump out mainly the preassembled amyloid fibrils (not light chains) from the blood stream into the subendothelial area as a physiologic function.

Determinants of phase angle in Japanese patients with diabetes.

Phase angle, obtained using bioelectrical impedance analysis, non-invasively reflects the whole-body cellular condition and nutritional status and may be helpful as a prognostic factor. Patients with diabetes had a smaller phase angle than healthy subjects. However, the clinical significance of phase angle has not yet been elucidated. Therefore, the purpose of this study was to clarify the relationship between phase angle and HbA1c in patients with diabetes and the clinical relevance of phase angle. A retrospective, multicenter, cross-sectional study was conducted with Japanese patients with diabetes. Body composition was determined with bioelectrical impedance analysis, and this was used to obtain phase angle. Phase angle was assessed in relation to clinical parameters, body composition parameters, and HbA1c levels. A total of 655 patients were enrolled (400 men and 255 women, aged 57.1 ± 14.8 years, body mass index 25.6 ± 5.2 kg/m2, HbA1c 8.1 ± 1.9%). Even in patients with diabetes, the phase angle was higher in men than in women and did not differ between the types of diabetes. Multiple regression analysis, performed with phase angle as the objective variable, and age, sex, diabetes type, HbA1c, albumin level, and body mass index as explanatory variables, revealed that phase angle was negatively affected by HbA1c (B = - 0.043, 95% Confidence interval: - 0.07 to - 0.02, p < 0.001). HbA1c, age, sex, albumin level, and body mass index were independent determinants of phase angle in participants with diabetes.

Distinct hypoglycemic effect of different formulations of a fixed ratio of basal insulin plus glucagon-like peptide-1 receptor agonist in a patient with pancreatic diabetes.

Fixed-ratio combination injection therapy (FRC) is a fixed-ratio mixture containing basal insulin and glucagon-like peptide-1 receptor agonist (GLP-1 RA) in a single injection for the treatment of patients with type 2 diabetes. The two types of FRC products contain different concentrations and mixing ratios of basal insulin and GLP-1 RA. Both products demonstrated satisfactory blood glucose control throughout the day, with less hypoglycemia and weight gain. However, few studies have examined the differences in the actions of the two formulations. Herein, we present a case of a 71-year-old man with pancreatic diabetes and significantly impaired intrinsic insulin secretion capacity, who demonstrated a marked difference in glycemic control following treatment with two different FRC formulations. Treatment with IDegLira, an FRC product, demonstrated suboptimal glucose control in the patient. However, after a change in therapy to another FRC product, IGlarLixi, his glucose control markedly improved, even with a decrease in the injection dose. This difference could have been due to lixisenatide, a short-acting GLP-1RA contained in IGlarLixi, which exerts a postprandial hypoglycemic effect irrespective of intrinsic insulin secretion capacity. In conclusion, IGlarLixi has the potential to achieve good fasting and postprandial glucose control with a once-daily injection, even in patients with type 2 diabetes who have a reduced intrinsic insulin secretion capacity. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-023-00621-5.

DI/cle, a Measure Consisting of Insulin Sensitivity, Secretion, and Clearance, Captures Diabetic States.

CONTEXT: Insulin clearance is implicated in regulation of glucose homeostasis independently of insulin sensitivity and insulin secretion. OBJECTIVE: To understand the relation between blood glucose and insulin sensitivity, secretion, and clearance. METHODS: We performed a hyperglycemic clamp, a hyperinsulinemic-euglycemic clamp, and an oral glucose tolerance test (OGTT) in 47, 16, and 49 subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes mellitus (T2DM), respectively. Mathematical analyses were retrospectively performed on this dataset. RESULTS: The disposition index (DI), defined as the product of insulin sensitivity and secretion, showed a weak correlation with blood glucose levels, especially in IGT (r = 0.04; 95% CI, -0.63 to 0.44). However, an equation relating DI, insulin clearance, and blood glucose levels was well conserved regardless of the extent of glucose intolerance. As a measure of the effect of insulin, we developed an index, designated disposition index/clearance, (DI/cle) that is based on this equation and corresponds to DI divided by the square of insulin clearance. DI/cle was not impaired in IGT compared with NGT, possibly as a result of a decrease in insulin clearance in response to a reduction in DI, whereas it was impaired in T2DM relative to IGT. Moreover, DI/cle estimated from a hyperinsulinemic-euglycemic clamp, OGTT, or a fasting blood test were significantly correlated with that estimated from 2 clamp tests (r = 0.52; 95% CI, 0.37 to 0.64, r = 0.43; 95% CI, 0.24 to 0.58, r = 0.54; 95% CI, 0.38 to 0.68, respectively). CONCLUSION: DI/cle can serve as a new indicator for the trajectory of changes in glucose tolerance.

Obesity and risk for its comorbidities diabetes, hypertension, and dyslipidemia in Japanese individuals aged 65 years.

Diabetes, hypertension, and dyslipidemia are obesity-related comorbidities that contribute to the development of cardiovascular disease, one of the leading causes of death. In addition to obesity, the underweight condition is a concern because it can give rise to sarcopenia, particularly after the age of 65 years. We examined the risk for diabetes, hypertension, and dyslipidemia due to obesity in individuals of this age. We retrospectively investigated the relation between obesity and its three major comorbidities in 10,852 individuals aged 65 years who underwent health checkups implemented by Kobe City between April 2017 and March 2021. The prevalence of diabetes, hypertension, and dyslipidemia with and without hyper-low-density lipoprotein-cholesterolemia was 9.7%, 41.0%, 63.8%, and 19.5%, respectively, and the prevalence of these conditions increased with increasing obesity. The risk for diabetes and hypertension was increased markedly (odds ratios of 12.95 and 19.44, respectively), and that for dyslipidemia with and without hyper-low-density lipoprotein-cholesterolemia was modestly increased (odds ratios of 2.59 and 3.65, respectively) at a BMI of ≥ 35 kg/m2 compared with normal weight. Analysis by gender revealed that the obesity-related risk for dyslipidemia with hyper-low-density lipoprotein-cholesterolemia was small compared with other comorbidities in women, while the risk for all comorbidities elevated similarly in men. Our results suggest the importance of public health intervention for obesity to suppress its comorbidities, especially diabetes and hypertension, at this age.

Preoperative Serum Cortisol Level Is Predictive of Weight Loss After Laparoscopic Sleeve Gastrectomy in Men with Severe Obesity but Not Women.

BACKGROUND: Bariatric surgery is an effective treatment for severe obesity and its associated medical problems. Preoperative factors that predict postoperative weight loss remain to be fully characterized, however. METHODS: Anthropometric and laboratory data were collected retrospectively for severely obese patients who underwent laparoscopic sleeve gastrectomy (LSG) between April 2016 and July 2019 at our hospital. Preoperative factors that predicted weight loss at 1 year after LSG were investigated. RESULTS: A total of 122 subjects (45 men and 77 women) underwent LSG. The mean ± SD age and body mass index at surgery were 44.4 ± 10.4 years and 40.7 ± 6.7 kg/m2. The percent total weight loss (%TWL) was 27.0 ± 8.6 among all subjects, 26.4 ± 8.0 among men, and 27.4 ± 8.9 among women, with no significant difference between the sexes. The %TWL showed a significant inverse correlation with serum cortisol level in men and with age and the visceral/subcutaneous fat area ratio in women. Multivariable regression analysis revealed the presence of type 2 diabetes and the serum cortisol concentration to be negatively associated with %TWL among all subjects and men, respectively. Receiver operating characteristic curve analysis identified an optimal cutoff of 10 µg/dL for prediction of a %TWL of ≥ 25 in men by serum cortisol level. CONCLUSIONS: Serum cortisol concentration was identified as a predictor for postoperative weight loss in men. Our results may thus help inform the decision to perform LSG or more effective surgical procedures in men with severe obesity.

Panhypopituitarism Mimicking Acute Coronary Syndrome.

A 59-year-old man suspected of having myocardial infarction with sinus bradycardia, a decreased blood pressure, and ST-change on an electrocardiogram was referred to our hospital's emergency department. Emergent coronary angiography revealed no significant findings. However, the patient experienced shock and required intensive care. Curiosity rose when his urination volume was not disturbed; we suspected hormonal abnormalities. A hormonal examination and imaging analysis revealed panhypopituitarism caused by a Rathke's cyst. Appropriate hormonal replacement therapy improved his symptoms and led to normalization of his electrocardiogram findings. Acute coronary syndrome (ACS) is a fatal disease; however, clinicians must not discount panhypopituitarism, as it may mimic ACS symptoms.

Glucocorticoid in Combination with a TNF-α Inhibitor: Treatment of Deep Vein Thrombosis in a Patient with Behçet's Disease.

A 38-year-old man with deep vein thrombosis associated with Behçet's disease (BD) was admitted to our hospital due to worsening symptoms despite the initiation of direct oral anticoagulants (DOACs). Administration of oral prednisolone and an intravenous anti-tumor necrosis factor-alpha (TNF-α) monoclonal antibody dramatically improved his symptoms. In addition, he was incidentally diagnosed with autosomal dominant polycystic kidney disease, which increases the risk of aortic aneurysms. BD also increases the risk of aortic aneurysms. This case suggests that immunosuppressive treatment is effective in patients with inflammation-related DOAC-refractory venous thrombosis who also suffer from BD.

Successful Resolution of Glucose Toxicity With the Use of Fixed-Ratio Combination Injection of Basal Insulin and Short-Acting Glucagon-Like Peptide 1 (GLP-1) Receptor Agonist.

Chronic hyperglycemia leads to a decrease in glucose-stimulated insulin secretion and an increase in insulin resistance. Resolving these glucose toxicities is pivotal in type 2 diabetes therapy because the decline in insulin secretion and insulin sensitivity causes further hyperglycemia. Conventionally, multiple daily insulin injection therapy was applied in such a situation. However, it could not be easily introduced, especially in outpatients. We present a case involving the successful resolution of glucose toxicity easily, immediately, and safely by using a fixed-ratio combination (FRC) injection of basal insulin and short-acting glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1 RA). Additionally, we discuss the advantages of this new injection therapy.

Hemophagocytic Syndrome-Like Tuberculosis-Immune Reconstitution Inflammatory Syndrome After the Initiation of Hepatic Tuberculosis Treatment.

A 25-year-old Nepalese woman was referred to our hospital because of fever and intermittent abdominal pain with inguinal lymphadenopathy, which had lasted for several months. A liver biopsy of the positron emission tomography-positive lesion led to a diagnosis of hepatic tuberculosis. After the initiation of antituberculosis treatment, her symptoms resolved. However, 11 days after treatment initiation, chest and back pain, high-grade fever, and vomiting appeared and gradually worsened. She developed anemia and her serum ferritin level was elevated. Hemophagocytic syndrome due to the initial deterioration of tuberculosis was suspected and steroid therapy was initiated with the continuation of the antituberculosis drugs. Thereafter, the patient's condition improved remarkably.

Biclonal Gammopathy as a Misleading Indicator to Diagnose POEMS Syndrome: An Autopsy Case Report and a Review of the Literature.

A 76-year-old man presented with a four-month history of progressive bilateral lower limb muscle weakness and dysesthesia. The patient had extravascular volume overload, and laboratory findings confirmed hypothyroidism, renal dysfunction, and chronic inflammation. Serum protein and immunofixation electrophoresis revealed biclonality of immunoglobulin A (IgA)-kappa and IgA-lambda, which was attributed to chronic inflammation. Subsequently, we detected the proliferation of monoclonal plasma cells in the bone marrow, which led to a diagnosis of POEMS syndrome. Despite the initiation of chemotherapy, the patient died of aspiration pneumonia. In this case, biclonal gammopathy in peripheral blood delayed a diagnosis of POEMS syndrome.

Acute Onset of Remitting Seronegative Symmetrical Synovitis With Pitting Edema (RS3PE) Two Weeks After COVID-19 Vaccination With mRNA-1273 With Possible Activation of Parvovirus B19: A Case Report With Literature Review.

Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is a rare clinical entity characterized by "remitting," "seronegative," and "symmetrical" synovitis with pitting edema on the dorsum of the hands and feet. Although rheumatic or malignant diseases are diseases that are known to coexist with RS3PE, other factors such as medication, infection, and vaccination have been reported to be associated with RS3PE. Here, we present a case of RS3PE syndrome that satisfied all four diagnostic criteria of RS3PE (pitting edema in the limbs, acute onset, age ≥ 50 years, and/or rheumatoid factor negativity) after mRNA-1273 SARS-CoV-2 vaccination.

Glycated albumin (GA) and the GA/HbA1c ratio are higher in diabetic patients positive for insulin antibodies with high binding capacity and low affinity.

Patients with diabetes mellitus having insulin antibodies (InsAb) with properties of high binding capacity and low affinity, which are observed in insulin autoimmune syndrome (IAS), are known to have greater plasma glucose fluctuations. Glycated albumin (GA) and the GA/HbA1c ratio have been demonstrated to reflect plasma glucose fluctuations. Hence, we hypothesized that GA or the GA/HbA1c ratio in diabetic patients having InsAb with properties of high binding capacity and low affinity may be higher than those in InsAb-negative diabetic patients, and we verified this hypothesis. Subjects were 12 diabetic patients who had InsAb noted while being treated with insulin and were subjected to Scatchard analysis and whose InsAb had properties similar to those of patients with IAS (affinity constant K1 < 0.24 × 1/10-8 M, number of binding sites R1 ≥ 11.5 × 10-8 M) [four cases of type 1 diabetes (T1D) and eight cases of type 2 diabetes (T2D)]. The control group consisted of T1D and T2D cases matched to the T1D and T2D cases, respectively, according to sex, age, BMI, and HbA1c. GA and the GA/HbA1c ratio were compared between both groups. GA and the GA/HbA1c ratio in InsAb-positive patients was significantly higher than that in the control group for both T1D and T2D patients. Diabetic patients having InsAb with properties of high binding capacity and low affinity had higher GA and the GA/HbA1c ratio than those of InsAb-negative patients. Greater plasma glucose fluctuations were suggested in InsAb-positive diabetic patients.

Accuracy of a Professional Continuous Glucose Monitoring Device in Individuals with Type 2 Diabetes Mellitus.

Among continuous glucose monitoring (CGM) devices, which continuously measure glucose concentration in subcutaneous interstitial fluid for comprehensive monitoring of blood glucose profile, only FreeStyle Libre Pro® (Abbott Diabetes Care) is currently available in Japan as a professional system. FreeStyle Libre Pro® is easy to use because it does not require calibration by self-monitoring of blood glucose (SMBG), but information on its accuracy has been insufficient. To evaluate the measurement accuracy of FreeStyle Libre Pro®, we have now compared blood glucose levels determined by this device with those measured by SMBG in 40 individuals with type 2 diabetes mellitus. The mean absolute relative difference (MARD) for FreeStyle Libre Pro® measurements compared with SMBG measurements was calculated as an index of CGM accuracy. Overall blood glucose values measured by SMBG were 167.0 ± 60.1 mg/dL, and those determined by FreeStyle Libre Pro® were 155.0 ± 60.7 mg/dL, with this difference being statistically significant. The MARD for FreeStyle Libre Pro® relative to SMBG was 12.7 ± 9.3%. It was substantially higher in 2 of the 40 patients, at 49.2% and 47.5%, than in the other 38 individuals. MARD values did not differ significantly between before and 2 h after meals. However, the MARD was significantly higher for SMBG values of <100 mg/dL than for those of ≥250 mg/dL. Our results thus indicate that the measurement accuracy of FreeStyle Libre Pro® is relatively good, but that some cases in which values determined by the device deviate from SMBG values require caution in interpretation.

Stereoselective Synthesis of Polysubstituted Tetrahydropyranones via Acid-Promoted Cyclization of ß-Silyl-γ-ethylidene-γ-butyrolactones with Aldehydes and Ketones.

ß-Silyl-γ-ethylidene-γ-butyrolactone upon one-pot treatment with aldehydes and ketones in the presence of Lewis acids underwent a tandem Hosomi-Sakurai/Prins cyclization to give polysubstituted tetrahydropyranones stereoselectively. Various aldehydes and ketones can be used in this reaction to produce the corresponding tetrahydropyranones. The optical purity of the starting γ-butyrolactone was substantially retained in the resulting tetrahydropyranones.

Relation of cardiac function to insulin resistance as evaluated by hyperinsulinemic-euglycemic clamp analysis in individuals with type 2 diabetes.

AIMS: Whereas homeostasis model assessment of insulin resistance (HOMA-IR), an easily measured but limited index of insulin resistance, has been shown to correlate with impairment of cardiac function in individuals without diabetes, the pathological relevance of insulin resistance to the development of cardiac dysfunction in individuals with type 2 diabetes has remained unclear. Here we investigated the relation between left ventricular (LV) function as assessed by echocardiography and insulin resistance as evaluated by hyperinsulinemic-euglycemic clamp analysis, the gold standard for measurement of this parameter, in individuals with type 2 diabetes. METHODS: This retrospective study included 34 individuals with type 2 diabetes who underwent both hyperinsulinemic-euglycemic clamp analysis and echocardiography. Both the insulin sensitivity index (ISI) as determined by glucose clamp analysis as well as HOMA-IR were determined as measures of insulin resistance. The ratio of the peak early- to late-diastolic mitral inflow velocities (E/A) and the LV ejection fraction (LVEF) were determined as measures of diastolic and systolic function, respectively. RESULTS: The ISI was significantly correlated with both the E/A ratio and LVEF (correlation coefficients of 0.480 and 0.360, respectively), whereas HOMA-IR was not correlated with either cardiac parameter. Multivariate analysis revealed that ISI was an independent predictor for both a high log [E/A] (P = 0.031) and a high LVEF (P = 0.045). CONCLUSIONS: Insulin resistance as evaluated by hyperinsulinemic-euglycemic clamp analysis may be causally related to LV diastolic and systolic dysfunction in individuals with type 2 diabetes.

Clinical features of 65-year-old individuals in Japan diagnosed with possible sarcopenia based on the Asian Working Group for Sarcopenia 2019 criteria.

AIM: The prevalence of sarcopenia and the health status of affected individuals, particularly among the young elderly, are unclear in Japan. We determined the prevalence of possible sarcopenia, a concept proposed by the Asian Working Group for Sarcopenia (AWGS) in 2019, and then investigated its clinical features in community-dwelling young elderly individuals in Kobe, a representative large city in Japan. METHODS: This retrospective cross-sectional study examined 1768 residents of Kobe aged 65 years who underwent health and frailty checkups implemented by Kobe City between April 2017 and March 2019. Possible sarcopenia was diagnosed by the AWGS 2019 algorithm. Frailty status was assessed with the use of the Kihon Checklist, which was developed to identify senior citizens requiring nursing care in Japan. RESULTS: Fifty-one of the 1768 subjects were diagnosed with possible sarcopenia (overall prevalence of 2.9% [confidence interval: 2.1-3.7%]), with the prevalence being higher in women than in men. Individuals with possible sarcopenia had a lower body mass index, abdominal circumference, diastolic blood pressure and percentage of taking lipid-lowering drugs as well as a higher high-density lipoprotein cholesterol level and estimated glomerular filtration rate. They also showed a higher degree of frailty. A low body mass index and physical inactivity were significantly associated with possible sarcopenia. CONCLUSIONS: The prevalence of possible sarcopenia based on the AWGS 2019 criteria was 2.9% among 65-year-olds in Japan, with affected individuals more likely to be frail compared with those without this condition. Geriatr Gerontol Int 2021; 21: 689-696.

Nontraumatic bladder rupture: The images before and after.

We should consider the complication of bladder rupture for patients with worsened abdominal pain and inability to pass urine following acute cystitis. A CT scan is a useful first-line modality when evaluating for a suspected bladder rupture.