Type 2 diabetes mellitus (T2DM) is a progressive metabolic disease that necessitates individualized therapeutic strategies focusing on both glycemic control and the mitigation of comorbidities. In recent years, sodium-glucose cotransporter-2 (SGLT2) inhibitors have emerged as a cornerstone of modern treatment due to their unique renal mechanism of action. This review summarizes the metabolic mechanisms, pleiotropic effects, and clinical significance of SGLT2 inhibitors in the management of T2DM. This review provides an updated overview of the metabolic and systemic effects of SGLT2 inhibition. By promoting glycosuria, SGLT2 inhibitors induce a negative energy balance that contributes to modest weight loss, improved body composition, and beneficial alterations in lipid metabolism. Beyond their metabolic effects, accumulating preclinical evidence suggests that SGLT2 inhibitors exert anti-inflammatory and antifibrotic actions, partly through modulation of macrophage polarization and attenuation of oxidative stress. The clinical utility of SGLT2 inhibitors is highlighted through the review of major cardiovascular and renal outcome trials, which confirm significant benefits in reducing heart failure hospitalizations and slowing the progression of chronic kidney disease. Finally, we integrate these findings into the context of the latest international guidelines while addressing safety profiles, the rationale for combination therapies, and the transition toward a personalized, risk-based management approach in T2DM.

Cushing's disease (CD) is a rare endocrine disorder caused by the overproduction of adrenocorticotrophin hormone (ACTH) from a pituitary tumour, leading to excessive secretion of cortisol. The chronic exposure to cortisol leads to endocrine and cardiovascular complications that persist even after remission of hypercortisolism. CD is associated with a significant clinical burden characterised by insulin resistance, renal dysfunction and cardiovascular complications. In addition, patients frequently experience impaired health-related quality of life (HRQoL) and have an increased risk of mortality. There are currently no approved therapies targeting these complications. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are antihyperglycaemic agents that target SGLT2 transporters in the renal proximal convoluted tubules, thus leading to glycosuria and reduction of glycaemia. Initially approved as anti-diabetic agents, SGLT2i have subsequently revealed to exert a wide range of beneficial effects, namely cardiorenal protection; therefore having been recently approved as a first-line treatment for chronic kidney disease and heart failure, regardless of the presence of diabetes. While the clinical and metabolic efficacy of SGLT2i has been extensively documented in type 2 diabetes, heart failure and chronic kidney disease, their systemic effects may also be relevant in patients with CD, who exhibit cardiovascular, renal and metabolic alterations even after biochemical remission. The myriad benefits of SGLT2i align closely with the unmet clinical needs for new medical treatment for patients with CD, supporting their potential therapeutic relevance in this disease. Accordingly, we herein review the pathophysiology, clinical presentation and treatment of CD, and explore the potential therapeutic benefit of SGLT2i in this disorder.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors, diabetic medicines, induce glucosuria to lower glycemia and energy reserve, initially reducing weight. The weight-reducing capacity substantially differs between individuals, likely due to both social/psychological factors and physical/metabolic states. Exclusively analyzing the contribution of physical/metabolic states is difficult in humans but feasible in mice. To explore whether metabolic states can alter weight outcomes of SGLT2 inhibitor treatment, the impact of canagliflozin was studied comparatively in high-fat-diet-induced obese (DIO) mice and leptin-receptor-deficient db/db mice. Canagliflozin, orally administered, induced rapid reductions in glycemia and weight followed by elevated food intake in both models. The initial weight loss was rebounded in db/db mice, but progressed and sustained in DIO mice accompanied by circadian rises in body temperature and locomotor activity, the effects possibly balancing the elevated food intake. These results reveal that physical/metabolic states, independent of social/psychological factors, influence weight outcome of canagliflozin treatment.

Sodium glucose cotransporter-2 (SGLT2) inhibitors are a class of antidiabetics with benefits including HbA1c-lowering, weight loss, cardiovascular and renal protection in addition to adverse effects including genitourinary tract infections, ketoacidosis, and bone loss. Here, we describe the rationale and design of the Genetics of Response to Canagliflozin (GRC) study and report on the pharmacodynamic findings. This study, for which enrollment has been completed, was conducted in healthy Amish individuals with a goal of identifying genetic predictors of variability in safety and efficacy of the SGLT2 inhibitor canagliflozin. Participants took canagliflozin 300 mg/day for 5 days, completed a 24-h urine collection, and had blood drawn at baseline, Day 3, and Day 6. The primary endpoint is glucosuria and the secondary endpoints assess additional biomarkers for safety and efficacy related to bone, cardiovascular disease, and ketosis. 402 participants completed the study. We identified significant variability in the degree of canagliflozin-induced glucosuria with a heritability of 34% (p = 8.69e-03). Canagliflozin induced significant increases in serum phosphorous (Day 3: +5.0%, p = 5.83e-21) and fibroblast growth factor-23 (Day 3: +20.2%, p = 1.58e-18), decrease in 1,25-dihydroxyvitamin D (Day 3: -25.0%, p = 5.71e-54), and increase in parathyroid hormone: (Day 3: +20.8%, p = 1.98e-33). Canagliflozin also significantly decreased serum uric acid (Day 6: -33.2%, p = 1.01e-65) and increased beta-hydroxybutyrate (Day 3: +71.9%, p = 8.11e-28). The most significant baseline characteristic associated with glucosuria was eGFR (p = 8.10e-10). This study will provide the opportunity to identify genetic and other 'omic predictors of safety and efficacy biomarkers for SGLT2 inhibitor response that could help guide diabetes treatment in the future.

Diabetic ketoacidosis (DKA) is a life-threatening acute metabolic complication of diabetes characterized by hyperglycemia, metabolic acidosis, and ketosis. Appropriate insulin therapy and glucose supplementation during treatment are essential to prevent persistent ketoacidosis. A 53-year-old man presented with a one-week history of polyuria. Urinalysis revealed 3+ ketonuria and 3+ glucosuria. Laboratory tests showed a hemoglobin A1c (HbA1c) level of 8.0%, plasma glucose at 720 mg/dL, arterial pH of 7.23, and bicarbonate (HCO3[-]) at 15.9 mEq/L. He was diagnosed with DKA and was immediately admitted for treatment with intravenous saline and continuous regular insulin infusion. Eight hours after the initiation of therapy, plasma glucose decreased to 169 mg/dL; however, saline infusion without glucose supplementation was continued. After 30 hours, he was transferred to the diabetes department while still receiving saline and a minimal insulin infusion rate (0.1 U/h). At that time, despite a plasma glucose level of 125 mg/dL, metabolic acidosis persisted (pH 7.28) with continued 3+ ketonuria, consistent with persistent ketoacidosis despite euglycemia during treatment of DKA. The treatment regimen was revised to include glucose-containing intravenous fluids and an appropriate insulin dose. Following this adjustment, metabolic acidosis resolved. Further evaluation revealed serum C-peptide at <0.03 ng/mL and anti-glutamic acid decarboxylase (GAD) antibody at <5.0 U/mL, leading to a diagnosis of fulminant type 1 diabetes. This case highlights that insufficient glucose supplementation and inadequate insulin administration during DKA management may result in persistent ketoacidosis despite normalization of plasma glucose levels.

Neonatal diabetes mellitus is a rare cause of persistent hyperglycemia in early infancy and is usually monogenic. We describe a male preterm neonate born at 34 weeks' gestation with intrauterine growth restriction who developed severe hyperglycemia from the first days of life. Plasma glucose reached a maximum of 570 mg/dL with persistent glycosuria, negative urine ketones, and a normal acid-base profile. C-peptide was profoundly suppressed (0.01 ng/mL), supporting marked endogenous insulin deficiency. Following optimization of glucose administration, intravenous short-acting regular human insulin was initiated with hourly glucose monitoring and complicated by early asymptomatic hypoglycemia requiring rapid correction and insulin dose reduction. As enteral feeds started, treatment was switched to micro-dosed subcutaneous short-acting regular human insulin with the use of a freshly prepared dilution and a pre-feed threshold strategy. Insulin requirements progressively decreased, and therapy was discontinued by three months of age with maintenance of normoglycemia and normal glycated hemoglobin (HbA1c). Growth and neurodevelopment were normal through two years of follow-up. This case highlights the importance of keeping neonatal diabetes in mind for preterm, growth-restricted infants with persistent severe hyperglycemia requiring insulin after exclusion of secondary causes, and also to master the details of practical safety considerations for insulin use in early life.