Effects of GLP-1RA and SGLT2i, Alone or in Combination, on Mouse Models of Type 2 Diabetes Representing Different Disease Stages.

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 ß-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.

Therapy Combining Glucagon-Like Peptide-1 Receptor Agonist with Sodium-Glucose Cotransporter 2 Inhibitor Suppresses Atherosclerosis in Diabetic ApoE-Deficient Mice.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) have beneficial effects on cardiovascular disease in addition to their glucose-lowering effects. In this study, the effects of these drugs, when used individually or in combination, on cardiovascular atherosclerotic lesion development were compared in diabetic ApoE-deficient (ApoE KO) hyperlipidemic mice. METHODS: ApoE-KO mice were treated with streptozotocin and nicotinamide, generating a type 2 diabetes model. The mice were randomly divided into four groups: vehicle-treated (untreated), liraglutide (LIRA), ipragliflozin (IPRA), and combination therapy (combo). These mice, as well as non-diabetic controls, were fed a high-fat diet. After 8 weeks of drug administration, the heart and aorta were removed and analyzed. RESULTS: Atherosclerotic lesions evaluated by oil red O (ORO) staining were significantly larger in the untreated group (13.4±0.8% of the total aortic area) than in the non-diabetic controls (4.4±0.5%, p<0.01), while being reduced in the combo group (6.0±1.0%, p<0.01) as compared with the untreated group. The ORO stain-positive area in the LIRA and IPRA groups tended to be reduced but their differences were not statistically significant. Transcript levels of Mcp1 and Sirt1 were significantly reduced and increased, respectively, in the combo compared with the untreated group, while no significant changes were observed in the monotherapy groups. CONCLUSIONS: The data suggest that combination therapy with liraglutide and ipragliflozin may be an efficient regimen for preventing the development of atherosclerosis in diabetic mice deficient in ApoE.

Glucagon Response to Glucose Challenge in Patients with Idiopathic Postprandial Syndrome.

BACKGROUND: Postprandial syndrome is characterized by hunger, weakness, and anxiety neurosis after meals. Although abnormal glucagon response is a suggested mechanism, inaccuracies in conventional glucagon measurement methods have prevented precise analysis. Recently, a more reliable dual-antibody sandwich enzyme-linked immunosorbent assay for glucagon was 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, glucagon concentration was measured with the novel method and analyzed retrospectively. RESULTS: Median (lower quartile, upper quartile) age and body-mass index were 40 years (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 µU/mL (6.8, 8.8) and reached 73.7 µU/mL (54.3, 82.6) at 30 min. Insulin remained elevated until 180 min. Fasting glucagon was 21.1 pg/mL (16.1, 33.8), reached a nadir of 6.9 (3.5, 10.3) at 60 min, one-third the baseline level, and remained suppressed until 180 min. We observed two types of glucagon dynamics: a lower fasting glucagon with further suppression and a normal or higher fasting glucagon with a subsequent large decrease. CONCLUSIONS: These data suggest that glucagon suppression is greater in patients with idiopathic postprandial syndrome than in previously studied healthy subjects. The present data will contribute to our understanding and future research of this syndrome.

Elsberg syndrome related to varicella zoster virus infection with painless skin lesions in an elderly woman with poorly controlled type 2 diabetes mellitus.

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.