Protocol of a Prospective Observational Study on Lifestyle and Quality of Life in Adults with Type 1 Diabetes in Japan.

INTRODUCTION: Recent studies have shown that the quality of life (QOL) of people living with type 1 diabetes (T1D) is poor and must be improved. However, the living situation and QOL of adults living with T1D in Japan have not been fully clarified. This study will examine their lifestyle, QOL, and clinical situation, as well as the relationships between them. METHODS: This is a prospective, 5-year follow-up observational study. Between December 2019 and September 2021, we enrolled adults in Japan who were living with T1D and receiving insulin therapy, and are acquiring longitudinal clinical data and the responses to seven questionnaires regarding lifestyle and QOL. The primary study outcomes are (1) the relationship between Problem Areas in Diabetes (PAID) scores and various factors including demographic data, clinical characteristics, medical history, lifestyle habits, treatment history, biochemical data, and the scores of questionnaires; and (2) the relationship between Beck Depression Inventory (BDI)-II scores and various factors aforementioned. The secondary outcomes are the relationships between various factors aforementioned and each of the following: (1) blood glucose control, (2) blood lipid control, (3) dietary patterns, (4) fear of hypoglycemia, (5) sleep patterns, and (6) physical activity. PLANNED OUTCOME: We registered 352 participants. The median age was 49 (41-63) years, and the median duration of T1D was 13 (8-20) years. All the results will be available in 2026. We expect to clarify the factors associated with decreased QOL, and that this knowledge will contribute to improving QOL in adults in Japan who are living with T1D and receiving insulin therapy. TRIAL REGISTRATION: Clinical Trials.gov identifier, UMIN000044088.

The Importance of Continuous Glucose Monitoring-derived Metrics Beyond HbA1c for Optimal Individualized Glycemic Control.

CONTEXT: Current guidelines recommend assessing glycemic control using continuous glucose monitoring (CGM) and hemoglobin A1c (HbA1c) measurement. OBJECTIVE: This study aimed to clarify the characteristics of patients who might benefit from CGM metrics in addition to HbA1c monitoring. METHODS: CGM metrics, specifically time in range (TIR), time below range (TBR), and time above range (TAR), were determined in 999 outpatients with type 2 diabetes and compared between HbA1c categories (HbA1c < 53 mmol/mol [7.0%, HbA1c <  53], HbA1c 53-63 mmol/mol [7.0-7.9%, HbA1c 53-63], HbA1c 64-74 mmol/mol [8.0-8.9%, HbA1c 64-74], and HbA1c ≥ 75 mmol/mol [9.0%, HbA1c ≥  75]) and between patients with identical HbA1c categories who were stratified by age, types of antidiabetic agents, and renal function. RESULTS: For HbA1c <  53 category, patients aged ≥ 65 years had a significantly higher nocturnal TBR than those aged < 65 years. For HbA1c <  53 and HbA1c 53-63 categories, patients receiving insulin and/or sulfonylureas had a significantly higher TAR and TBR, and a lower TIR than those not receiving these drugs, and for HbA1c 64-74 category, they had a significantly higher TBR. For HbA1c <  53, HbA1c 53-63, and HbA1c 64-74 categories, patients with an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 had a significantly higher TBR during some periods than those with an eGFR ≥ 60. CONCLUSION: Higher HbA1c levels do not always protect against hypoglycemic episodes. Our data demonstrate that using CGM metrics to complement HbA1c monitoring is beneficial, especially in older people, users of insulin and/or sulfonylureas, and patients with chronic kidney disease.

Cyclic AMP/cAMP-GEF pathway amplifies insulin exocytosis induced by Ca2+ and ATP in rat islet beta-cells.

BACKGROUND: Cyclic AMP (cAMP) plays a pivotal role in insulin secretion induced by incretins. The effects of the second messenger extend to many sites and there has been much controversy on the mechanisms. The aim of this study was to examine how cAMP amplified insulin exocytosis. METHODS: Rat islets were permeabilized with alpha-toxin to measure insulin exocytosis in the fixed conditions of Ca(2+) and ATP. The effects of several agents on insulin exocytosis were observed in perifusion experiments. RESULTS: Cyclic AMP enhanced the Ca(2+)-induced insulin release by around 30%, independent of Ca(2+) concentrations between 10 and 3000 nmol/L. A cAMP-GEF selective cAMP analogue, 8-(4-chloro-phenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate, also amplified insulin release. The effect disappeared in the absence of ATP. Conversely, cAMP-independent gradual increase in insulin release was observed with ATP. These results suggested that the site of action of cAMP-GEF existed proximal to that of ATP. An analogue selective to PKA, N(6)-Benzoyladenosine-3',5'-cyclic monophosphate, had little effect. Also, a PKA-selective inhibitor, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide, reduced insulin releases induced by 1000 nmol/L Ca(2+), but did not influence the relative increase produced by Ca(2+) and cAMP. CONCLUSION: Cyclic AMP potentiated Ca(2+) and ATP-induced exocytosis to a similar relative extent independent of Ca(2+) concentrations. The process appeared to be mainly mediated by cAMP-GEF. In addition, the cAMP/cAMP-GEF pathway may enhance insulin release by replenishing the readily releasable pool.

Thyrotropin-producing pituitary adenoma associated with Graves' disease.

OBJECTIVES: The examination of potential associations between Graves' disease and thyrotropin-producing pituitary adenoma (TSHoma) after treatment using octreotide, and of the expression of peroxisome proliferator-activated receptor gamma (PPAR gamma). DESIGN AND METHODS: A specimen of resected TSHoma tissue from our case was immunohistochemically examined for expression of somatostatin receptor 2A (SSTR2A) and PPAR gamma. Specimens of thyroid tissue from two cases with Hashimoto's thyroiditis were immunohistochemically examined for expression of SSTR2A. RESULTS: Expression of SSTR2A and PPAR gamma was identified in TSHoma cells. SSTR2A was also expressed in lymphocytes that had infiltrated thyroid tissue in Hashimoto's thyroiditis. In previous reports, three of four patients with TSHoma displayed Graves' disease after tumor resection, and TSH is also known to play a major role in regulating immunomodulatory gene expression in thyrocytes. CONCLUSIONS: Both the immunomodulatory effects of octreotide on intrathyroidal lymphocytes and rapid reductions in TSH may contribute to the onset of Graves' disease. Patients with TSHoma-associated autoimmune thyroiditis should undergo careful follow-up for development of Graves' disease after treatment. Both octreotide and the PPAR gamma receptor-activating ligands, thiazolidinediones, may be effective for patients with TSHoma.

Strongest correlation of HbA(1c) with 1-month-earlier glucose levels in type 2 diabetes.

We examined the correlations of hemoglobin A(1c) (HbA(1c)) with each plasma glucose (PG) level obtained at 0 (the same day), 1 and 2 month(s) prior to HbA(1c) determination. Data were from glycemic profiles of four patients of type 2 diabetes mellitus treated with tablets whose HbA(1c) and pre- and post-breakfast PG levels were monitored each month. There was no significant difference in the correlation coefficients in cases 1 and 2, who presented with linear glycemic time courses. In contrast, HbA(1c) correlated with 1-month-earlier pre-breakfast PG level more strongly than 2-month-earlier post-breakfast PG level in cases 3 and 4, and than same-day post-breakfast PG level in case 3 (P<0.05, ANOVA). The cases 3 and 4 presented with fluctuating glycemic time courses. Samples were separated into upslope's and downslope's sections according to HbA(1c) fluctuation in the latter two cases. Reflecting around the 1-month lag between HbA(1c) and PG, the two sections' regression lines for PG versus HbA(1c) corresponded in the only samples related to 1-month-earlier pre- and post-breakfast PG (t-test). In conclusion, it appears that pre- and post-breakfast PG levels are the most reliable predictors of 1-month-later HbA(1c) in type 2 diabetic outpatients who undergo medical examinations every month.

Successful treatment of Good syndrome with cytomegalovirus duodenoenteritis using a combination of ganciclovir and immunoglobulin with high anti-cytomegalovirus antibody titer.

We describe the case of a 64-year-old woman with Good syndrome who presented with watery diarrhea and abdominal distention caused by cytomegalovirus (CMV) duodenoenteritis. Thymoma and hypogammaglobulinemia were first identified when the patient was 58 years old. She had repeatedly complained of symptoms even after thymectomy. Abdominal radiography revealed multiple air-fluid levels, and computed tomography revealed ascites and dilation of the small intestine. Immunofluorescent staining of specimens obtained by duodenal mucosal biopsy revealed intracellular inclusion bodies of CMV, although serum CMV pp65 antigenemia assays yielded negative results. CMV infection of the small intestine caused mucosal edema resulting in malabsorption. The patient was treated using ganciclovir and an immunoglobulin preparation with a high titer of antibodies against CMV (CMV-Ig), and subsequently made a rapid recovery from abdominal symptoms. When patients with Good syndrome complain of abdominal symptoms, particularly chronic diarrhea, a diagnosis of CMV gastroenteritis should not be excluded, even if negative results are obtained for CMV pp65 antigenemia assays. Combination therapy of ganciclovir and CMV-Ig seems useful for patients with CMV gastroenteritis.

Brachial-ankle pulse wave velocity is useful for evaluation of complications in type 2 diabetic patients.

Pulse wave velocity (PWV) is useful for the evaluation of aortic stiffness. The brachial-ankle PWV (baPWV) and carotid PWV (from heart to carotid) were compared to study the relation of these two types of PWVs to diabetic complications in patients with type 2 diabetes mellitus. The baPWV was determined by oscillometrically measuring the pulse volume record at the upper arm and ankles. The carotid PWV was measured tonometrically. Ninety patients with type 2 diabetes mellitus were divided into tertile groups on the basis of baPWV or carotid PWV. The correlations of these variables with albuminuria, peripheral neuropathy, coefficient of variation of R-R intervals (CV R-R) on the electrocardiogram at rest, and retinopathy were examined by logistic regression analysis. After adjustment for age, systolic blood pressure, and duration of diabetes, logistic regression analysis showed that baPWV was directly related to the frequencies of albuminuria, decreased CV R-R, peripheral neuropathy, and retinopathy. In contrast, carotid PWV did not significantly correlate with any diabetic complications. We conclude that oscillometrically determined baPWV is related to the risk of diabetic microvascular disease in patients with type 2 diabetes mellitus and suggested to be useful for assessing risk factors of diabetic complications.

Association of upregulated activity of K(ATP) channels with impaired insulin secretion in UCP1-expressing insulinoma cells.

Insulin-secreting MIN6 cells overexpressing uncoupling protein-1 (UCP1) were studied regarding insulin secretion in response to various secretagogues. Overexpression of UCP1 prevented an increase of cytosolic ATP levels induced by glucose. In contrast, glucose utilization was not affected, nor was glycerol phosphate flux. The UCP1-expressing cells showed an inability to increase cytosolic Ca(2+) concentration ([Ca(2+)](i)) in response to glucose or alpha ketoisocaproate and this resulted in less insulin secretion, whereas initial reduction in [Ca(2+)](i) occurring upon either nutrient addition was not affected. Moreover, the effectiveness of tolbutamide on [Ca(2+)](i) increase was reduced and the dose-response relations for insulin secretion induced by the agent was shifted toward the right in the UCP1-expressing cells. The resting membrane potential of the UCP1-expressing cells was significantly hyperpolarized by 6.2 mV compared with control cells. In the perforated and conventional whole-cell patch-clamp configurations, the conductance density of ATP-sensitive K(+) (K(ATP)) channels of the UCP1-expressing cells was 6-fold and 1.7-fold greater than that of the control cells, respectively. The sensitivity of K(ATP) channels for tolbutamide was not different between two groups, indicating that in intact cells more than 6-fold higher concentrations of tolbutamide were required to reduce the K(ATP) channel currents of UCP1-expressing cells to the same levels as of the control cells. The current density of the voltage-dependent Ca(2+) channels was not influenced. In conclusion, UCP1-expressing cells showed a refractoriness to respond to tolbutamide as well as nutrients. An upregulated activity of K(ATP) channels was associated with unresponsiveness to the agent in the cells with impaired mitochondrial function.