Aims/Introduction: Non‐alcoholic fatty liver disease (NAFLD) is often observed in individuals with type 2 diabetes mellitus, and it is known that the presence of type 2 diabetes mellitus leads to the aggravation of NAFLD. The aim of this study was to compare the possible effects of three kinds of oral hypoglycemic agents on NAFLD in individuals with type 2 diabetes mellitus.Materials and Methods: We carried out a prospective clinical trial (a randomized and open‐label study) in patients with type 2 diabetes mellitus and NAFLD. A total of 98 patients were randomly allocated either to the dapagliflozin (n = 32), pioglitazone (n = 33) or glimepiride (n = 33) group, and the patients took these drugs for 28 weeks. The primary end‐point was the change of the liver‐to‐spleen ratio on abdominal computed tomography.Results: There was no difference in baseline clinical characteristics among the three groups. Dapagliflozin, pioglitazone and glimepiride ameliorated hyperglycemia similarly. Bodyweight and visceral fat area were significantly decreased only in the dapagliflozin group. Serum adiponectin levels were markedly increased in the pioglitazone group compared with the other two groups. Dapagliflozin and pioglitazone, but not glimepiride, significantly increased the liver‐to‐spleen ratio, and the effects of dapagliflozin and pioglitazone on the liver‐to‐spleen ratio were comparable.Conclusions: The present study showed that the decrease of visceral fat area and the increase of adiponectin level contributed to the improvement of NAFLD in patients with type 2 diabetes mellitus. Furthermore, dapagliflozin and pioglitazone exerted equivalent beneficial effects on NAFLD in patients with type 2 diabetes mellitus, although it seemed that these two drugs had different mechanisms of action.

While there are various kinds of drugs for type 2 diabetes mellitus at present, in this review article, we focus on metformin which is an insulin sensitizer and is often used as a first-choice drug worldwide. Metformin mainly activates adenosine monophosphate-activated protein kinase (AMPK) in the liver which leads to suppression of fatty acid synthesis and gluconeogenesis. Metformin activates AMPK in skeletal muscle as well, which increases translocation of glucose transporter 4 to the cell membrane and thereby increases glucose uptake. Further, metformin suppresses glucagon signaling in the liver by suppressing adenylate cyclase which leads to suppression of gluconeogenesis. In addition, metformin reduces autophagy failure observed in pancreatic β-cells under diabetic conditions. Furthermore, it is known that metformin alters the gut microbiome and facilitates the transport of glucose from the circulation into excrement. It is also known that metformin reduces food intake and lowers body weight by increasing circulating levels of the peptide hormone growth/differentiation factor 15 (GDF15). Furthermore, much attention has been drawn to the fact that the frequency of various cancers is lower in subjects taking metformin. Metformin suppresses the mechanistic target of rapamycin (mTOR) by activating AMPK in pre-neoplastic cells, which leads to suppression of cell growth and an increase in apoptosis in pre-neoplastic cells. It has been shown recently that metformin consumption potentially influences the mortality in patients with type 2 diabetes mellitus and coronavirus infectious disease (COVID-19). Taken together, metformin is an old drug, but multifaceted mechanisms of action of metformin have been unraveled one after another in its long history.

Fundamental pancreatic β-cell function is to produce and secrete insulin in response to blood glucose levels. However, when β-cells are chronically exposed to hyperglycemia in type 2 diabetes mellitus (T2DM), insulin biosynthesis and secretion are decreased together with reduced expression of insulin transcription factors. Glucagon-like peptide-1 (GLP-1) plays a crucial role in pancreatic β-cells; GLP-1 binds to the GLP-1 receptor (GLP-1R) in the β-cell membrane and thereby enhances insulin secretion, suppresses apoptotic cell death and increase proliferation of β-cells. However, GLP-1R expression in β-cells is reduced under diabetic conditions and thus the GLP-1R activator (GLP-1RA) shows more favorable effects on β-cells at an early stage of T2DM compared to an advanced stage. On the other hand, it has been drawing much attention to the idea that GLP-1 signaling is important in arterial cells; GLP-1 increases nitric oxide, which leads to facilitation of vascular relaxation and suppression of arteriosclerosis. However, GLP-1R expression in arterial cells is also reduced under diabetic conditions and thus GLP-1RA shows more protective effects on arteriosclerosis at an early stage of T2DM. Furthermore, it has been reported recently that administration of GLP-1RA leads to the reduction of cardiovascular events in various large-scale clinical trials. Therefore, we think that it would be better to start GLP-1RA at an early stage of T2DM for the prevention of arteriosclerosis and protection of β-cells against glucose toxicity in routine medical care.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors facilitate urine glucose excretion by reducing glucose reabsorption, leading to ameliorate glycemic control. While the main characteristics of type 2 diabetes mellitus are insufficient insulin secretion and insulin resistance, SGLT2 inhibitors have some favorable effects on pancreatic β-cell function and insulin sensitivity. SGLT2 inhibitors ameliorate fatty liver and reduce visceral fat mass. Furthermore, it has been noted that SGLT2 inhibitors have cardio-protective and renal protective effects in addition to their glucose-lowering effect. In addition, several kinds of SGLT2 inhibitors are used in patients with type 1 diabetes mellitus as an adjuvant therapy to insulin. Taken together, SGLT2 inhibitors have amazing multifaceted effects that are far beyond prediction like some emerging magical medicine. Thereby, SGLT2 inhibitors are very promising as relatively new anti-diabetic drugs and are being paid attention in various aspects. It is noted, however, that SGLT2 inhibitors have several side effects such as urinary tract infection or genital infection. In addition, we should bear in mind the possibility of diabetic ketoacidosis, especially when we use SGLT2 inhibitors in patients with poor insulin secretory capacity.

Sodium-glucose cotransporter 2 inhibitor tofogliflozin is a new type of antidiabetic drug for individuals with type 2 diabetes mellitus (T2DM). The aim of this study was to examine in which type of individuals and/or under which conditions tofogliflozin could exert more beneficial effects on body composition and/or glycemic control in Japanese individuals with T2DM. We retrospectively evaluated the effects of tofogliflozin on body composition and/or glycemic control in individuals with T2DM who newly started taking tofogliflozin. After tofogliflozin treatment, body weight was significantly reduced and HbA1c levels were significantly decreased. Body fat mass, skeletal muscle mass, and skeletal muscle index, a marker for sarcopenia, were also reduced after the treatment. In univariate analyses, there was a statistically significant association between the decrease of HbA1c level after tofogliflozin treatment (Δ HbA1c) and the following parameters such as HbA1c levels at baseline, visceral fat area (VFA) at baseline, and reduction of VFA after the treatment (Δ VFA). Furthermore, in multivariate analyses, HbA1c levels at baseline and duration of diabetes were independently associated with Δ HbA1c. These results suggest that tofogliflozin would be more suitable for relatively obese individuals whose duration of diabetes is relatively short.

Various important transcription factors in the pancreas are involved in the process of pancreas development, the differentiation of endocrine progenitor cells into mature insulin-producing pancreatic β-cells and the preservation of mature β-cell function. However, when β-cells are continuously exposed to a high glucose concentration for a long period of time, the expression levels of several insulin gene transcription factors are substantially suppressed, which finally leads to pancreatic β-cell failure found in type 2 diabetes mellitus. Here we show the possible underlying pathway for β-cell failure. It is likely that reduced expression levels of MafA and PDX-1 and/or incretin receptor in β-cells are closely associated with β-cell failure in type 2 diabetes mellitus. Additionally, since incretin receptor expression is reduced in the advanced stage of diabetes mellitus, incretin-based medicines show more favorable effects against β-cell failure, especially in the early stage of diabetes mellitus compared to the advanced stage. On the other hand, many subjects have recently suffered from life-threatening coronavirus infection, and coronavirus infection has brought about a new and persistent pandemic. Additionally, the spread of coronavirus infection has led to various limitations on the activities of daily life and has restricted economic development worldwide. It has been reported recently that SARS-CoV-2 directly infects β-cells through neuropilin-1, leading to apoptotic β-cell death and a reduction in insulin secretion. In this review article, we feature a possible molecular mechanism for pancreatic β-cell failure, which is often observed in type 2 diabetes mellitus. Finally, we are hopeful that coronavirus infection will decline and normal daily life will soon resume all over the world.