Metformin is a biguanide, a drug class of herbal origin that has been widely used to treat diabetes since the 1950s. Two other biguanides were withdrawn from clinical use because they caused lactic acidosis. Currently, metformin is the first-line medication for treatment of type 2 diabetes mellitus (T2DM) in most guidelines. Animal and human studies have shown that metformin acts in the liver, where it inhibits gluconeogenesis through multiple pathways. In addition, metformin has been shown to be an insulin sensitizer, likely acting in the gut lumen through multiple mechanisms. However, a full understanding of metformin's mechanism of action remains elusive, and the drug's effects are likely pleiotropic. In view of its efficacy and safety for T2DM, attention has been given to the repurposing of metformin as a component of adjunct therapy for cancer, age-related diseases, and inflammatory diseases. In this review, we outline the effectiveness, safety, and precautions in the clinical use of metformin, and discuss recent advances in our understanding of the mechanisms of its action.

Incretins, including GIP (glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide) and GLP-1 (glucagon-like peptide-1), are intestinal hormones secreted following oral ingestion, exerting insulinotropic effects. Since the levels of incretins are also affected by the order in which nutrients are ingested, the timing of meals, and chewing, diet therapy considering incretin secretion is thought to be effective for the glycemic management of patients with type 2 diabetes. Because incretin-related drugs ameliorate hyperglycemia by enhancing insulin secretion in a glucose-dependent manner and by suppressing glucagon secretion, their associated hypoglycemia risk is low when administered alone and they are unlikely to cause weight gain. Incretin-related drugs include DPP-4 (dipeptidyl peptidase-4) inhibitors, GLP-1 receptor agonists, and GIP/GLP-1 receptor agonists. GLP-1 receptor agonists in particular are known to prevent the incidence or progression of cardiovascular events and diabetic nephropathy, and are therefore strongly recommended in American and European treatment guidelines. On the other hand, there is no evidence for the preventive effects DPP-4 inhibitors against diabetic complications, and caution is warranted regarding their use in relation to drug-specific adverse effects. Here we review the importance of dietary intervention when using incretin-related drugs.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce blood glucose levels by inhibiting glucose reabsorption from primary urine via SGLT2, expressed in the proximal renal tubule. Although SGLT2 inhibitors were initially developed as a treatment for diabetes mellitus, several clinical trials revealed that they reduced the risk of heart and renal failure, irrespective of glucose intolerance. SGLT2 inhibitors bring multifaceted benefits when used safely, but have a notable side effect that warrants caution: euglycemic ketoacidosis. To mitigate this risk, attention to dietary management is crucial. Specifically, it is important not to follow a low-carbohydrate diet. Additionally, it is recommended to discontinue SGLT2 inhibitors before any major planned surgery and to withdraw them in the event of severe emergency hospitalization. During periods of fasting, it is essential to adequately supplement glucose intravenously.

Dietary therapy is essential for treatment of diabetes, and it is important to understand the involvement of nutrients in insulin secretion and blood glucose regulation. Insulin secretion is regulated by three pathways: the triggering pathway, the metabolic amplifying pathway, and the neuro-hormonal amplifying pathway. Glucose plays a major role in the triggering pathway, while fatty acids are closely related to the incretin-mediated amplifying pathway. Diabetes mellitus results from absolute or relative inadequacy of these insulin actions. To prevent postprandial elevation of the blood glucose level, it is necessary to select foods with a low glycemic index (GI) and, especially for type 1 diabetes, to adjust the insulin dose at meal times by carbocounting in order to achieve good control. In reality, however, lipids and proteins also have a complex association with blood glucose regulation, and therefore limitations exist. As there are many different types of insulin, in some cases it may be necessary to choose the right insulin for the diet of each individual.

Prevention of type 2 diabetes requires intervention with factors that induce insulin resistance. Although blood fatty acids have been implicated in insulin resistance, the relationship between blood fatty acids and insulin resistance in young Japanese adults has remained unclear. In this study, we examined the associations between odd-chain saturated fatty acids (OcSFAs) and even-chain fatty acids (EcFAs) in the serum phospholipid (PL), cholesterol ester (CE), and free fatty acid (FFA) fractions with homeostatic model assessment for insulin resistance (HOMA-IR) in non-diabetic young Japanese adults. In addition, we explored lifestyle factors affecting fatty acids associated with HOMA-IR. Participants (n＝39, 20.6±1.2 years, females; 56％) underwent physical activity assessment (IPAQ), a dietary survey (BDHQ), body composition measurement, and fasting blood sampling. Serum levels of lipids, insulin (IRI), and fasting blood glucose (FPG) were measured using commercial kits, and the fatty acid composition in each lipid fraction was analyzed by GC-MS following separation using thin-layer chromatography. HOMA-IR was calculated from IRI and FPG. The composition of OcSFAs in the serum PL fraction was negatively associated with HOMA-IR in females (r＝－0.510, p＝0.015). However, no association was found between the OcSFA composition and lifestyle factors or nutrients. On the other hand, in males, there was no significant association between the OcSFA composition in serum PL and HOMA-IR, suggesting a gender difference in this association.