Patients with diabetes mellitus (DM) are at increased risk of infections, with the urinary tract being the most frequent infection site. Incomplete bladder emptying, frequent urination and abdominal distension are typical symptoms of urinary tract infections (UTIs). A 68-year-old female with a long history of poorly controlled type 2 DM (T2DM) visited our hospital complaining of urinary retention, which was initially diagnosed as cystitis by another doctor. The urologist at our hospital identified a skin rash extending from the left hip to her genital area. A dermatologist was consulted. She was clinically diagnosed with herpes zoster (HZ) involving the left sacral dermatome area. As Elsberg syndrome (ES) was suspected, a lumbar puncture was performed, revealing aseptic meningitis associated with varicella zoster virus (VZV) infection. Intravenous acyclovir with urinary catheterization in combination with methylprednisolone pulse therapy resulted in a good clinical course. HZ very uncommonly involves sacral dermatomes, but it can develop in patients with prolonged poorly controlled DM. Furthermore, early diagnosis can be difficult when patients have diabetic peripheral neuropathy, which may mask symptoms related to skin lesions. Because this disease is potentially severe, detailed examination is important for clinicians managing patients with DM who have complaints indicative of urinary tract disorders.
Glucagon-like peptide-1 receptor agonist (GLP-1RA) and sodium-dependent glucose transporter 2 inhibitor (SGLT2i), in addition to lowering glucose, have pleiotropic effects on the heart, kidneys, and liver. These drugs have thus come into widespread use for treating type 2 diabetes (T2DM). However, mechanistic comparisons and effects of combining these drugs have not been adequately studied. Employing diet-induced obese (DIO) mice and db/db mice as models of the early and advanced stages of T2DM, we evaluated effects of single or combined use of liraglutide (a GLP-1RA) and ipragliflozin (a SGLT2i). Treatments with liraglutide and/or ipragliflozin for 28 days improved glycemic control and reduced hepatic lipid accumulation similarly in DIO mice. In contrast, in db/db mice, despite similar favorable effects on fatty liver, liraglutide exerted no beneficial effects on glycemic control. Improved glycemic control in db/db mice treated with ipragliflozin was accompanied by increased pancreatic β-cell area and insulin content, both of which tended to rise further when ipragliflozin was combined with liraglutide. Our data suggest that liraglutide is more efficient at an earlier stage and ipragliflozin can be effective in both stages. In addition, their combined use is a potential option for treating advanced stage diabetes with fatty liver disease.
Background: Postprandial syndrome is characterized by hunger, weakness and anxiety neurosis occurring after meals. Although abnormal glucagon response has been suggested, inaccuracies of the conventional glucagon measurement method have prevented from precise analysis. Recently, a more reliable dual-antibody sandwich enzyme-linked immunosorbent assay for glucagon has been developed. Methods:We conducted a 75 g oral glucose tolerance test (OGTT) extending to 4 hours in 14 patients with idiopathic postprandial syndrome. In addition to blood glucose and insulin, we have measured glucagon concentrations using the novel method and analyzed retrospectively.Results: Median (lower quartile, upper quartile) of age and BMI were 40 years old (30, 49) and 24.9 (23.1, 26.2), respectively. The OGTT revealed that one patient had a diabetic pattern, and two were glucose intolerant. Fasting insulin was 7.6 U/mL (6.8, 8.8) and reached 73.7 (54.3, 82.6) at 30 min. Insulin remained elevated until 180 min. The fasting glucagon was 21.1 pg/mL (16.1, 33.8), falling at 60 min to a nadir of 6.9 (3.5, 10.3), onethird of the baseline, then remaining suppressed until 180 min. Furthermore, we have found that two types of glucagon dynamics: one is lower fasting glucagon with further suppression and the other is normal or higher fasting glucagon with subsequent big drop.Conclusions: These data suggest that glucagon suppression is stronger in patients with idiopathic postprandial syndrome than in normal subjects previously reported. The present data will contribute to further understanding and future research of this syndrome.
Glucose produces, through glycolysis, pyruvate, a substrate for mitochondrial metabolism. Mitochondrial metabolism generates signals for insulin exocytosis, which include ATP and other as yet unidentified molecules. Although important roles of mitochondrial metabolism of glucose for insulin secretion is established, roles of glycolysis are not completely understood. Does glycolysis merely produce pyruvate for mitochondrial metabolism or generate its own signal? To study this question, we have created mitochondrial pyruvate carrier 2 (Mpc2) knockout MIN6 cells by the Crispr technology. We first generated MIN6 cells expressing MPC2-Flag under the control of Tet3G transcriptional activator, to assure mitochondrial metabolism of glucose in a condition of Mpc2 alleles being knocked out. Then, stop codons followed by the zeocin or puromycin-resistant gene units were introduced in the second exons of the gene. We have confirmed a complete loss of endogenous MPC2 expression by Western blot analyses and these cells were maintained in the presence of doxycycline, expressing MPC2-Flag. Upon withdrawal of doxycycline, glycolytic flux estimated by 5-[3H]glucose utilization was unaltered at 5 mM glucose but reduced by 37.2% ± 1.2% (Mean ± SE, n = 3, p < 0.05) at 12.5 mM and 55.3% ± 9.6% (p < 0.05) at 20 mM. In MPC2-deficient MIN6 cells, glucose-stimulated insulin secretion was completely abolished at 12.5 and 20 mM glucose, while glutamine (5 mM) plus leucine (5 mM) induced insulin secretion was comparable to that by doxycycline-treated MPC2-Flag expressing cells. Interestingly, when MPC2-deficient MIN6 cells were activated with glutamine plus leucine, 5-20 mM glucose was able to cause further dose-dependent increases in insulin secretion with 1.9 ± 0.3-fold (n = 4, p < 0.05) augmentation at 20 mM. These data suggested that glycolysis generates signals for insulin secretion distinct from those produced by the mitochondria in glucose-stimulated insulin secreting cells. Disclosure H. Ishihara: Advisory Panel; Self; Astellas Pharma Inc. Research Support; Self; Daiichi Sankyo, Eli Lilly Japan K.K., Kowa Company, Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi. H. Nishioka: None. M. Yamana: None. A. Nagasawa: None. M. Kosuda: None. M. Koike: None. G. Kohno: None. H. Saito: None.
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