Administration, Oral ; Glucose Transporter Type 2 ; metabolism ; Humans ; Intestinal Absorption ; physiology ; Organic Anion Transporters ; metabolism ; Peptide Transporter 1 ; Pharmacokinetics ; Sodium-Glucose Transporter 1 ; metabolism ; Symporters ; metabolism

Familial renal glycosuria (FRG) is an inherited disorder characterized by persistent glycosuria in the absence of hyperglycemia. It is caused by mutations in the sodium-glucose co-transporter, leading to increase in the renal excretion of glucose and sodium. However, there have been no studies on the role of fasting and postprandial changes in the urinary sodium excretion in patients with FRG. We report a case of renal glycosuria, which was confirmed by a SLC5A2 mutation via gene sequencing, and compared the postprandial urinary glucose and sodium excretion. A 26-year-old man sometimes experienced glycosuria on routine screening; however, other laboratory findings were normal. His fasting and postprandial urinary glucose excretion levels were 295mg/dL and 2,170mg/dL, respectively. The fasting and postprandial urinary sodium excretion levels were 200mEq/L and 89mEq/L, respectively. In patients with FRG, excessive diuresis might be prevented by a compensatory mechanism that reduces postprandial sodium excretion.
Adult ; Diuresis ; Fasting ; Glucose ; Glycosuria* ; Glycosuria, Renal ; Humans ; Hyperglycemia ; Mass Screening ; Renal Elimination ; Sodium ; Sodium-Glucose Transport Proteins

The management of type 2 diabetes mellitus should comprise healthy lifestyle modifications along with tailored pharmacologic treatment. Traditionally, the American Diabetes Association (ADA)'s Diabetes Management Guidelines have not prioritized specific anti-diabetic drugs over others with regard to cardiovascular disease (CVD) and mortality prevention. Recently, two novel anti-diabetic medications proved to be significantly protective against future CVD and mortality, regardless of the glycemic levels achieved in type 2 diabetic patients with pre-existing CVD. The 2018 ADA Guidelines recommend SGLT2 inhibitor and/or GLP-1 receptor agonist be used for type 2 diabetes patients with atherosclerotic CVD after metformin monotherapy failure. Considering the value of CVD protection in the management of diabetes mellitus, this minor guideline adjustment could have far-reaching implications.
Cardiovascular Diseases ; Diabetes Mellitus ; Diabetes Mellitus, Type 2 ; Glucagon-Like Peptide-1 Receptor ; Humans ; Life Style ; Metformin ; Mortality ; Sodium-Glucose Transporter 2

OBJECTIVETo reveal the effects and related mechanisms of chlorogenic acid (CGA) on intestinal glucose homeostasis.

METHODSForty male Sprague-Dawley rats were randomly and equally divided into four groups: normal chow (NC), high-fat diet (HFD), HFD with low-dose CGA (20 mg/kg, HFD-LC), and HFD with high-dose CGA (90 mg/kg, HFD-HC). The oral glucose tolerance test was performed, and fast serum insulin (FSI) was detected using an enzyme-linked immunosorbent assay. The mRNA expression levels of glucose transporters (Sglt-1 and Glut-2) and proglucagon (Plg) in different intestinal segments (the duodenum, jejunum, ileum, and colon) were analyzed using quantitative real-time polymerase chain reaction. SGLT-1 protein and the morphology of epithelial cells in the duodenum and jejunum was localized by using immunofluorescence.

RESULTSAt both doses, CGA ameliorated the HFD-induced body weight gain, maintained FSI, and increased postprandial 30-min glucagon-like peptide 1 secretion. High-dose CGA inhibited the HFD-induced elevation in Sglt-1 expression. Both CGA doses normalized the HFD-induced downregulation of Glut-2 and elevated the expression of Plg in all four intestinal segments.

CONCLUSIONAn HFD can cause a glucose metabolism disorder in the rat intestine and affect body glucose homeostasis. CGA can modify intestinal glucose metabolism by regulating the expression of intestinal glucose transporters and Plg, thereby controlling the levels of blood glucose and insulin to maintain glucose homeostasis.

Animals ; Chlorogenic Acid ; pharmacology ; Diet, High-Fat ; adverse effects ; Glucagon-Like Peptide 1 ; metabolism ; Glucose ; metabolism ; Glucose Tolerance Test ; Glucose Transporter Type 2 ; metabolism ; Homeostasis ; Insulin ; blood ; Intestines ; drug effects ; metabolism ; Male ; Proglucagon ; metabolism ; Random Allocation ; Rats, Sprague-Dawley ; Sodium-Glucose Transporter 1 ; metabolism ; Weight Gain ; drug effects

Sodium-glucose co-transporters are a family of glucose transporter found in the intestinal mucosa of the small intestine (SGLT-2) and the proximal tubule of the nephron (SGLT-1 and SGLT-2). They contribute to renal glucose reabsorption and most of renal glucose (about 90%) is reabsorbed by SGLT-2 located in the proximal renal tubule. Selectively inhibiting activity of SGLT-2 is an innovative therapeutic strategy for treatment of type 2 diabetes by enhancing urinary glucose excretion from the body. Therefore SGLT-2 inhibitors are considered to be potential antidiabetic drugs with an unique mechanism. This review will highlight some recent advances and structure-activity relationships in the discovery and development of SGLT-2 inhibitors including O-glycoside, C-glycoside, C, O-spiro glycoside and non glycosides.
Animals ; Benzhydryl Compounds ; chemical synthesis ; chemistry ; pharmacology ; Diabetes Mellitus, Type 2 ; drug therapy ; Glucosides ; chemical synthesis ; chemistry ; pharmacology ; Humans ; Hypoglycemic Agents ; chemical synthesis ; chemistry ; pharmacology ; Molecular Structure ; Monosaccharides ; chemical synthesis ; chemistry ; pharmacology ; Sodium-Glucose Transporter 1 ; metabolism ; Sodium-Glucose Transporter 2 ; antagonists & inhibitors ; metabolism ; Structure-Activity Relationship

The potential mechanism by which sodium-glucose cotransporter 2 (SGLT2) inhibitors prevent cardiovascular disease (CVD) is being widely investigated. Improved insulin resistance, along with decreased body fat mass associated with SGLT2 inhibitor treatment is consistent with previously well-established factors contributing to the prevention of CVD. These factors are responsible for reduction of oxidative stress as well as improvement of systemic inflammation. Because heart failure was one of the most dramatically improved cardiovascular events in various clinical trials and because SGLT2 inhibitors promote osmotic diuresis and natriuresis, hemodynamic changes are considered as a critical mechanism responsible for the cardioprotective effect of SGLT2 inhibitors. Restored tubuloglomerular feedback by SGLT2 inhibitors might play a role in renoprotection, which in turn, leads to fewer CVDs. Finally, blood ketone body increments in response to SGLT2 inhibition might act as a “super-fuel” for salvaging the failing diabetic heart.
Adipose Tissue ; Cardiovascular Diseases ; Diabetes Mellitus ; Diuresis ; Heart ; Heart Failure ; Hemodynamics ; Inflammation ; Insulin Resistance ; Ketones ; Natriuresis ; Oxidative Stress ; Sodium-Glucose Transport Proteins

Objective To assess the efficiency and safety of a novel sodium-glucose co-transporter 2 (SGLT2) inhibitor-SGLT2 inhibitors, in combination with insulin for type 1 diabetes mellitus (T1DM). Methods We searched Medline, Embase, and the Cochrane Collaboration Library to identify the eligible studies published between January 2010 and July 2016 without restriction of language. The Food and Drug Administration (FDA) data and ClinicalTrials (http://www.clinicaltrials.gov) were also searched. The included studies met the following criteria: randomized controlled trials; T1DM patients aged between 18 and 65 years old; patients were treated with insulin plus SGLT2 inhibitors for more than 2 weeks; patients' glycosylated hemoglobin (HbA1c) levels were between 7% and 12%. The SGLT2 inhibitors group was treated with SGLT2 inhibitors plus insulin, and the placebo group received placebo plus insulin treatment. The outcomes should include one of the following items: fasting blood glucose, HbA1c, glycosuria, or adverse effects. Data were analyzed by two physicians independently. The risk of bias was evaluated by using the Cochrane Collaboration's Risk of Bias tool and heterogeneity among studies was assessed using Chi-square test. Random effect model was used to analyze the treatment effects with Revman 5.3.Results Three trials including 178 patients were enrolled. As compared to the placebo group, SGLT2 inhibitor absolutely decreased fasting blood glucose [mean differences (MD) -2.47 mmol/L, 95% confidence interval (CI) -3.65 to -1.28, P<0.001] and insulin dosage (standardized MD -0.75 U, 95%CI -1.17 to -0.33, P<0.001). SGLT2 inhibitors could also increase the excretion of urine glucose (MD 131.09 g/24 h, 95%CI 91.79 to 170.39, P<0.001). There were no significant differences in the incidences of hyperglycemia [odds ratio (OR) 1.82, 95%CI 0.63 to 5.29, P=0.27], urinary tract infection (OR 0.95, 95%CI 0.19 to 4.85, P=0.95), genital tract infection (OR 0.27, 95%CI 0.01 to 7.19, P=0.43), and diabetic ketoacidosis (OR 6.03, 95%CI 0.27 to 135.99, P=0.26) between the two groups.Conclusion SGLT2 inhibitors combined with insulin might be an efficient and safe treatment modality for T1DM patients.
Adolescent ; Adult ; Aged ; Blood Glucose ; metabolism ; Diabetes Mellitus, Type 1 ; blood ; drug therapy ; Drug Therapy, Combination ; methods ; Fasting ; blood ; Female ; Glycated Hemoglobin A ; metabolism ; Humans ; Hypoglycemic Agents ; adverse effects ; therapeutic use ; Insulin ; adverse effects ; therapeutic use ; Male ; Middle Aged ; Randomized Controlled Trials as Topic ; Sodium-Glucose Transporter 2 ; antagonists & inhibitors

PURPOSE: Diabetic nephropathy (DN) is a prevalent chronic microvascular complication of diabetes mellitus involving disturbances in electrolytes and the acid-base balance caused by a disorder of glucose metabolism. NHE1 is a Na+/H+ exchanger responsible for keeping intracellular pH (pHi) balance and cell growth. Our study aimed to investigate roles of NHE1 in high glucose (HG)-induced apoptosis in renal tubular epithelial cells. MATERIALS AND METHODS: Renal epithelial tubular cell line HK-2 was cultured in medium containing 5 mM or 30 mM glucose. Then, cell apoptosis, oxidative stress, NHE1 expression, and pHi were evaluated. NHE1 siRNA and inhibitor were used to evaluate its role in cell apoptosis. RESULTS: HG significantly increased cell apoptosis and the production of reactive oxygen species (ROS) and 8-OHdG (p<0.05). Meanwhile, we found that HG induced the expression of NHE1 and increased the pHi from 7.0 to 7.6 after 48 h of incubation. However, inhibiting NHE1 using its specific siRNA or antagonist DMA markedly reduced cell apoptosis stimulated by HG. In addition, suppressing cellular oxidative stress using antioxidants, such as glutathione and N-acetyl cysteine, significantly reduced the production of ROS, accompanied by a decrease in NHE1. We also found that activated cyclic GMP-Dependent Protein Kinase Type I (PKG) signaling promoted the production of ROS, which contributed to the regulation of NHE1 functions. CONCLUSION: Our study indicated that HG activates PKG signaling and elevates the production of ROS, which was responsible for the induction of NHE1 expression and dysfunction, as well as subsequent cell apoptosis, in renal tubular epithelial cells.
Antioxidants/metabolism ; Apoptosis/*drug effects ; Cation Transport Proteins/*metabolism ; Cell Cycle/drug effects ; Cell Line ; Dose-Response Relationship, Drug ; Epithelial Cells/*cytology/drug effects/*metabolism ; Glucose/*pharmacology ; Glutathione/metabolism ; Humans ; Kidney Tubules/*cytology ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Sodium-Hydrogen Antiporter/*metabolism

The employment of sodium-glucose cotransporter 2 (SGLT-2) inhibitors in the treatment of diabetes mellitus and diabetic kidney disease (DKD) becomes a hot topic in recent years. Compared with traditional glucose-lowering drugs, SGLT-2 inhibitors present distinctive advantages in renal and cardiovascular protection. The mechanisms for renal protection include attenuating glomerular hyperfiltration, lowering serum uric acid, alleviating tubular lesions and regulating intrarenal renin-angiotensin-aldosterone system (RAAS) dysfunction. In addition, the lowering blood pressure, blunting blood glucose fluctuation, increasing insulin sensitivity, optimizing energy metabolism and body fat distribution account for the cardiovascular protective effects of SGLT-2 inhibitors. However, their potential adverse reactions and safety concerns should be carefully addressed in clinical usage.
Diabetes Mellitus, Type 2 ; Diabetic Nephropathies ; drug therapy ; Humans ; Hypoglycemic Agents ; pharmacology ; Sodium-Glucose Transporter 2 ; Sodium-Glucose Transporter 2 Inhibitors ; pharmacology ; Uric Acid

We aimed to identify the clinical variables associated with a better glucose-lowering response to the sodium glucose cotransporter 2 inhibitor ipragliflozin in people with type 2 diabetes mellitus (T2DM). We especially focused on urinary glucose excretion (UGE). This was a single-arm multicenter prospective study. A total of 92 people with T2DM aged 20 to 70 years with glycosylated hemoglobin (HbA1c) levels ≥7.0% and ≤9.5% were enrolled. Ipragliflozin (50 mg) was added to the background therapy for these people for 12 weeks. After 3 months treatment with ipragliflozin, the mean HbA1c levels were decreased from 7.6% to 6.9% and 62.0% of the people reached the HbA1c target of less than 7.0% (P<0.001). In addition, body weight, blood pressure, and lipid parameters were improved after ipragliflozin treatment (all P<0.001). The baseline HbA1c (r=0.66, P<0.001) and morning spot urine glucose to creatinine ratio (r=−0.30, P=0.001) were independently associated with the HbA1c reduction. Ipragliflozin treatment for 12 weeks improves glycemic control and other metabolic parameters. A higher HbA1c and lower UGE at baseline predicts a better glucose-lowering efficacy of ipragliflozin.
Blood Pressure ; Body Weight ; Creatinine ; Diabetes Mellitus, Type 2 ; Glucose ; Glycosuria ; Hemoglobin A, Glycosylated ; Prospective Studies ; Sodium ; Sodium-Glucose Transporter 2