Accuracy and Time Delay of Glucose Measurements of Continuous Glucose Monitoring and Bedside Artificial Pancreas During Hyperglycemic and Euglycemic Hyperinsulinemic Glucose Clamp Study

Background: Glucose values of continuous glucose monitoring (CGM) have time delays compared with plasma glucose (PG) values. Artificial pancreas (STG-55, Nikkiso, Japan) (AP), which measures venous blood glucose directly, also has a time delay because of the long tubing lines from sampling vessel to the glucose sensor. We investigate accuracy and time delay of CGM and AP in comparison with PG values during 2-step glucose clamp study. Methods: Seven patients with type 2 diabetes and 2 healthy volunteers were included in this study. CGM (Enlite sensor, Medtronic, CA) was attached on the day before the experiment. Hyperglycemic (200 mg/dL) clamp was performed for 90 minutes, followed by euglycemic (100 mg/dL) hyperinsulinemic (100 μU/mL) clamp for 90-120 minutes using AP. CGM sensor glucose was calibrated just before and after the clamp study. AP and CGM values were compared with PG values. Results: AP values were significantly lower than PG values at 5, 30 minute during hyperglycemic clamp. In comparison, CGM value at 0 minute was significantly higher, and its following values were almost significantly lower than PG values. The time delay of AP and CGM values to reach maximum glucose levels were 5.0 ± 22.3 (NS) and 28.6 ± 32.5 (p<0.05) min, respectively. Mean absolute rate difference of CGM was significantly higher than AP (24.0 ± 7.6 vs. 15.3 ± 4.6, p < 0.05) during glucose rising period (0-45 min), however, there are no significant difference during other periods. Conclusions: Both CGM and AP failed to follow plasma glucose values during non-physiologically rapid glucose rising, however, indicated accurate values during physiological glucose change

Urinary adiponectin in DKD

Aims: Since diabetes-associated kidney complication changes from diabetic nephropathy to diabetic kidney disease (DKD), more suitable biomarkers than urinary albumin are required. It has been hypothesized that urinary adiponectin (u-ADPN) is associated with the progression of DKD. We therefore evaluated the effectiveness of u-ADPN in predicting the decline of the renal function in patients with diabetes prior to end-stage renal disease. Methods: An ultrasensitive immune complex transfer enzyme immunoassay (ICT-EIA) was used to measure total and high molecular weight (HMW) adiponectin separately. We evaluated the relationships between the creatinine-adjusted urinary total-ADPN and HMW-ADPN, albumin (UACR) and liver-type fatty acid binding protein (L-FABP) at baseline and the 2-year change of the estimated glomerular filtration rate (ΔeGFR). Results: This 2-year prospective observational study included 201 patients with diabetes. These patients were divided into three groups according to their ΔeGFR: ≤-10 ml/min/1.73m2, >-10 and ≤0 ml/min/1.73m2, and >0 ml/min/1.73m2. Jonckheere-Terpstra test showed that lower ΔeGFR was associated with higher u-HMW-ADPN (p = 0.045). In logistic regression analysis, u-HMW-ADPN was associated with ΔeGFR after adjusted age, sex, and basal eGFR. Conclusion: Urinary HMW-ADPN could predict a declining renal function in patients with diabetes

Sarcopenia and AGEs in type 1 diabetes

Accumulation of advanced glycation end-products (AGEs) is thought to contribute to muscle weakness in a diabetic animal model. Skin autofluorescence is a proposed marker for accumulation of AGEs in the skin. We aimed to investigate the relationship between AGEs accumulation, sarcopenia and muscle function of Japanese patients with type 1 diabetes. A total of 36 patients with type 1 diabetes participated in the present cross-sectional study. Sarcopenia parameters (skeletal muscle mass index and knee extension strength) were compared with subcutaneous AGEs accumulation using skin autofluorescence. The prevalence of sarcopenia and impaired knee extension strength was 16.6% (men 0.0%, women 22.2%) and 47.2% (men 22.2%, women 55.6%), respectively. Knee extension strength was negatively correlated with skin autofluorescence (r² = 0.14, P < 0.05), but not with skeletal muscle mass index. In conclusion, the AGEs accumulation might be one of the reasons of impaired lower limb muscle function in Japanese patients with type 1 diabetes

Basal insulin ratio of type 1 diabetes

Aims/Introduction: To investigate the basal insulin requirement in patients with type 1 diabetes who are on multiple daily injections (MDI) and to assess the patient characteristics that affect the percent of total daily basal insulin dose to the total daily insulin dose (%TBD/TDD). Materials and Methods: The subjects of this study were 67 inpatients with type 1 diabetes who were served diabetic meals of 25–30 kcal/kg standard body weight during several weeks of hospitalization. The basal insulin requirement was adjusted to keep the blood glucose level from bedtime to before breakfast within a 30 mg/dL difference. The bolus insulin dose before the meal was adjusted to keep the blood glucose level below 140 and 200 mg/dL before and 2 h after each meal, respectively. The total daily insulin dose (TDD), the percent of total daily basal insulin dose (TBD) to TDD (%TBD/TDD), and clinical characteristics were collected. Results: The median (Q1, Q3) of TDD was 33.0 (26.0, 49.0) units, and the %TBD/TDD was 24.1 ± 9.8%. The %TBD/TDD was positively correlated with the body mass index (BMI) and negatively correlated with the age at the onset and at the examination according to a univariate analysis. However, the %TBD/TDD was dependent on the BMI (β = 0.340, P = 0.004) and the age at examination (β = −0.288, P = 0.012) according to the multiple regression analysis. Conclusions: The average %TBD/TDD in patients with type 1 diabetes on MDI was approximately 24% under inpatient conditions. The basal insulin requirement was dependent on the BMI and the age at examination

A case of isolated ACTH deficiency that required 6 months for the diagnosis from onset

A 53-year-old man noticed anorexia, nausea, and arthralgia of the upper limbs in April, 201X. Since these symptoms persisted, he visited general hospital and clinic and was examined for blood chemistry, ECG, echocardiography and so on. However, he did not get a definitive diagnosis and was followed up with drip infusion of saline. The symptoms did not subside and fatigue and syncope with hypotension developed. Furthermore, he also suffered weight loss of 10 kg in few months and was referred to our hospital for more detailed examinations in October, 201X. Upon the initial examination, all his symptoms matched those of adrenal insufficiency and notable decreases of both plasma ACTH and serum cortisol level were observed. Prompt glucocorticoid supplementation improved his symptoms and the abnormal laboratory data immediately. He was diagnosed adrenal insufficiency due to isolated ACTH deficiency from the results of CRH loading test and insulin tolerance test. Since most of the symptoms and laboratory findings are non-specific, diagnosis of adrenal insufficiency is often delayed. However, adrenal insufficiency could worsen when the patient is under stress (e.g. infection) and often be life-threatening. Glucocorticoid replacement therapy should be initiated as soon as the diagnosis is confirmed. Furthermore, educating patients and his families plays a very important role in the management of chronic adrenal insufficiency, in particular to the prevention of adrenal crisis

A case of Cushing’s syndrome detected by repeated fragility fractures

A ３８-year-old woman had suffered from an avulsion fracture of the left cuboid bone, a rib fracture, a fatigue fracture of the left second metatarsal bone and a pubic fracture within the last ４ years. She also realized that her face was getting rounded and became aware of edema on extremities. She had repeated fragile fractures before menopause and was referred to our department on suspicion of secondary osteoporosis. The patients showed physical signs of moon face, central obesity, and abdominal violaceous striae. Cushing’s syndrome was suspected, therefore confirmatory studies were performed. Circadian variation of cortisol : serum cortisol１９．３μg／dL（at７：００）, ２１．４μg／dL（at２３：００）, urinary free cortisol :２４７．４μg／２４h, ACTH :２．５pg／mL. Low-dose（１mg） dexamethasone did not suppress cortisol level（１８．９μg/dL）. Based on these findings, we diagnosed as Cushing’s syndrome and glucocorticoid excess seemed to be the cause of secondary osteoporosis. Abdominal CT identified a ２．７ cm tumor in the left adrenal gland, and in-phase T１‐weighted MRI showed decreased signal compared to out-phase, suggesting an adrenocortical adenoma. She underwent laparoscopic left adrenalectomy. Postoperative fasting serum cortisol decreased to２．２ μg/dL, and glucocorticoid replacement therapy was started. It is necessary to find out any secondary causes for premenopausal women with fragility fractures. It is well known that endocrine disorders including Cushing’s syndrome are the most frequent associated diseases in patients with premenopausal osteoporosis. Cushing’s syndrome should be considered as a causative disease in premenopausal women with osteoporosis

Novel method for detection of pancreatic beta cell death using cell-free DNA

In people with type１ diabetes（T１D）, biomarkers that can sensitively and quantitatively evaluate injury of pancreatic beta cell are required in order to predict the onset of the disease at an early stage and to provide interventions to prevent the progression of the disease. We developed a new method for quantifying pancreatic beta cell-derived insulin DNA in circulation that combines bisulfite conversion and Amplification Refractory Mutation System（ARMS）PCR, which can be performed using a conventional real-time PCR system. We applied this method to T１D patients and healthy adults, both could be detected in about ３０％ of cases. The results in healthy adults indicate that this method may have sensitivity to detect the turnover of pancreatic beta cells at physiological conditions. In post-onset T１D patients, there were many negatives because the amount of residual pancreatic beta cells was extremely small. However, in some cases with a short duration of the disease, pancreatic beta cell-derived insulin DNA was detected in negative correlation between the duration of the disease, that suggested the residual pancreatic beta cells continue to be slowly destroyed. It was demonstrated that the time course of pathophysiology in T１D could be understood using this method

The efficacy of incretin therapy in patients with type 2 diabetes undergoing hemodialysis

BACKGROUND: Although incretin therapy is clinically available in patients with type 2 diabetes undergoing hemodialysis, no study has yet examined whether incretin therapy is capable of maintaining glycemic control in this group of patients when switched from insulin therapy. In this study, we examined the efficacy of incretin therapy in patients with insulin-treated type 2 diabetes undergoing hemodialysis. METHODS: Ten type 2 diabetic patients undergoing hemodialysis received daily 0.3 mg liraglutide, 50 mg vildagliptin, and 6.25 mg alogliptin switched from insulin therapy on both the day of hemodialysis and the non-hemodialysis day. Blood glucose level was monitored by continuous glucose monitoring. After blood glucose control by insulin, patients were treated with three types of incretin therapy in a randomized crossover manner, with continuous glucose monitoring performed for each treatment. RESULTS: During treatment with incretin therapies, severe hyperglycemia and ketosis were not observed in any patients. Maximum blood glucose and mean blood glucose on the day of hemodialysis were significantly lower after treatment with liraglutide compared with treatment with alogliptin (p < 0.05), but not with vildagliptin. The standard deviation value, a marker of glucose fluctuation, on the non-hemodialysis day was significantly lower after treatment with liraglutide compared with treatment with insulin and alogliptin (p < 0.05), but not with vildagliptin. Furthermore, the duration of hyperglycemia was significantly shorter after treatment with liraglutide on both the hemodialysis and non-hemodialysis days compared with treatment with alogliptin (p < 0.05), but not with vildagliptin. CONCLUSIONS: The data presented here suggest that patients with type 2 diabetes undergoing hemodialysis and insulin therapy could be treated with incretin therapy in some cases

Dynapenia and AGEs in type 2 diabetes

Aims/Introduction: Advanced glycation end-products (AGEs), which are a major cause of diabetic vascular complications, accumulate in various tissues under chronic hyperglycemic conditions, as well as with aging in patients with diabetes. The loss of muscle mass and strength, so-called sarcopenia and dynapenia, has recently been recognized as a diabetic complication. However, the influence of accumulated AGEs on muscle mass and strength remains unclear. The present study aimed to evaluate the association of sarcopenia and dynapenia with accumulated AGEs in patients with type 2 diabetes. Materials and Methods: We recruited 166 patients with type 2 diabetes aged ≥30 years (mean age 63.2 ± 12.3 years; body mass index 26.3 ± 4.9 kg/m2; glycated hemoglobin 7.1 ± 1.1%). Skin autofluorescence as a marker of AGEs, limb skeletal muscle mass index, grip strength, knee extension strength and gait speed were assessed. Results: Sarcopenia and dynapenia were observed in 7.2 and 13.9% of participants, respectively. Skin autofluorescence was significantly higher in patients with sarcopenia and dynapenia. Skin autofluorescence was the independent determinant for skeletal muscle mass index, grip strength, knee extension strength, sarcopenia and dynapenia. Conclusions: Accumulated AGEs could contribute to reduced muscle mass and strength, leading to sarcopenia and dynapenia in patients with type 2 diabetes

Insulinoma with symptoms of suspected transient ischemic attack : A case report

We report the case of a６７-year-old woman who had symptoms suggestive of a transient ischemic attack（TIA）, such as lightheadedness and transient visual changes before meals for ４ months. She experienced altered consciousness before lunch and was taken to the emergency room２weeks ago. She had repeated hypoglycemia with a blood glucose level of ３１ mg/dL. Insulin secretion was not suppressed, with an immunoreactive insulin level of １４．０ μU/mL and connecting peptide immunoreactivity of １．８３ ng/mL for occasional blood glucose levels of ４９ mg/dL. Dynamic CT revealed a １７‐mm mass enhanced during the arterial phase in the pancreatic uncinate process, suggestive of a pancreatic neuroendocrine tumor. A selective arterial secretagogue（calcium）injection test revealed the localization of insulinoma in the head of the pancreas. Therefore, pancreatoduodenectomy was performed. Hyperglycemia occurred after the surgery, and it was judged that the insulinoma was resected. This case showed TIA-like symptoms without signs of sympathetic overdrive associated with hypoglycemia. Thus, the diagnosis was delayed. Insulinoma may present with symptoms of neuroglycopenia but not autonomic activity due to hypoglycemia. Insulinoma should be distinguished in patients with unknown neurological symptoms since neuroglycopenia caused by insulinoma is diverse