Sodium-Glucose Co-Transporter 2 Inhibitors and the Risk of Genitourinary Infections at HbA1c ≥10%: A Population Health-Based Retrospective Review.

BACKGROUND: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are first-line treatment for type 2 diabetes. Evidence has shown a 3- to 5-fold increase in the risk of genitourinary infections with their use due to inhibition of renal glucose reabsorption, resulting in glucosuria. Increased glucosuria is thought to increase the risk of genitourinary infections at a greater degree in patients with a significantly elevated HbA1c (≥10%), and initiation of SGLT2i is often delayed in these patients. While a limited body of evidence exists indicating that A1c level is not an independent risk factor for SGLT2i-induced genitourinary infection, pragmatically this concern remains a barrier to SGLT2i utilization. OBJECTIVE: Evaluate the real-world genitourinary (GU) infection rate in patients receiving SGLT2i with a baseline HbA1c ≥10% compared to patients with a baseline HbA1c <10%. METHODS: This retrospective cohort study evaluated data from 5542 adult patients treated between January 2013 and January 2023, who were prescribed an SGLT2i. Data collected included sex, age, race/ethnicity, renal function, date of SGLT2i start, number of SGLT2i orders, name and dose of SGLT2i, HbA1c, and a predetermined set of diagnosis codes related to bacterial and fungal genitourinary infections. The primary outcome was the overall GU infection rate after SGLT2i initiation within groups of baseline HbA1c of ≥10% and <10%, and the secondary outcome was total GU infections within these same groups. RESULTS: The primary outcome was equivalent between those with HbA1c <10% and HbA1c ≥10% (0.0064 ± 0.0565 vs 0.0030 ± 0.0303 infection per month [mean ± standard deviation]; P < 0.0001 for both lower and upper bounds). There was no statistically significant difference in total GU infections between the same groups (0.027 ± 0.21 vs 0.015 ± 0.14, P = 0.11). Female gender and prior recurrent infection were associated with increased GU infection after SGLT2i. CONCLUSION AND RELEVANCE: A baseline HbA1c ≥ 10% was not significantly associated with an increased risk of GU infection following the initiation of SGLT2i compared to those with a baseline HbA1c of <10%.

Performance of the ACMG-AMP criteria in a large familial renal glucosuria cohort with identified SLC5A2 sequence variants.

Familial Renal Glucosuria (FRG) is a co-dominantly inherited trait characterized by orthoglycaemic glucosuria. From 2003 to 2015 we have reported several cohorts validating SLC5A2 (16p11.2), encoding SGLT2 (Na+/glucose cotransporter family member 2), as the gene responsible for FRG. The aim of this work was to validate the variants identified in our extended FRG cohort of published, as well more recent unreported cases, according to the ACMG-AMP 2015 criteria. Forty-six variants were evaluated, including 16 novel alleles first described in this study. All are rare, ultra-rare or absent from population databases and most are missense changes. According to the ACMG-AMP standards, only 74% of the variants were classified as P/LP. The lack of descriptions of unrelated patients with similar variants or failing to test additional affected family members, averted a conclusion for pathogenicity in the alleles that scored VUS, highlighting the importance of both family testing and variant reporting. Finally, the cryo-EM structure of the hSGLT2-MAP17 complex in the empagliflozin-bound state improved the ACMG-AMP pathogenicity score by identifying critical/functional protein domains.

Renal Deletion of LRRC8/VRAC Channels Induces Proximal Tubulopathy.

BACKGROUND: Volume-regulated anion channels (VRACs) are heterohexamers of LRRC8A with LRRC8B, -C, -D, or -E in various combinations. Depending on the subunit composition, these swelling-activated channels conduct chloride, amino acids, organic osmolytes, and drugs. Despite VRACs' role in cell volume regulation, and large osmolarity changes in the kidney, neither the localization nor the function of VRACs in the kidney is known. METHODS: Mice expressing epitope-tagged LRRC8 subunits were used to determine the renal localization of all VRAC subunits. Mice carrying constitutive deletions of Lrrc8b-e, or with inducible or cell-specific ablation of Lrrc8a, were analyzed to assess renal functions of VRACs. Analysis included histology, urine and serum parameters in different diuresis states, and metabolomics. RESULTS: The kidney expresses all five VRAC subunits with strikingly distinct localization. Whereas LRRC8C is exclusively found in vascular endothelium, all other subunits are found in the nephron. LRRC8E is specific for intercalated cells, whereas LRRC8A, LRRC8B, and LRRC8D are prominent in basolateral membranes of proximal tubules. Conditional deletion of LRRC8A in proximal but not distal tubules and constitutive deletion of LRRC8D cause proximal tubular injury, increased diuresis, and mild Fanconi-like symptoms. CONCLUSIONS: VRAC/LRRC8 channels are crucial for the function and integrity of proximal tubules, but not for more distal nephron segments despite their larger need for volume regulation. LRRC8A/D channels may be required for the basolateral exit of many organic compounds, including cellular metabolites, in proximal tubules. Proximal tubular injury likely results from combined accumulation of several transported molecules in the absence of VRAC channels.

Gestational glycosuria, proteinuria, and borderline hypertension in pregnancy are predictors for the later onset of maternal chronic disease.

AIM: Although hypertensive disorders of pregnancy and gestational diabetes mellitus (DM) are risk factors for hypertension, DM, and kidney disease in later life, the association of gestational glycosuria, proteinuria, and borderline hypertension with these chronic diseases has been unclear. METHODS: This cross-sectional study was conducted between April 2017 and November 2020 at a Japanese tertiary hospital. Three variables listed in the Maternal and Child Health Handbook were analyzed: glycosuria, proteinuria, and systolic blood pressure (<130, 130-139, and ≥ 140 mmHg) during pregnancy. The incidences of DM, kidney disease, and hypertension self-reported by mothers of pregnant women on a questionnaire were assessed with logistic regression analysis. RESULTS: The 312 women completed the questionnaires an average of 35.8 ± 4.2 years after delivering their daughters. Risk for DM was significantly increased among women with glycosuria (adjusted odds ratio [aOR], 3.62; 95% confidence interval [CI], 1.21-10.9), and risk for kidney disease was significantly increased among women with proteinuria (aOR, 4.07; 95% CI, 1.29-12.9). Risk for hypertension was significant in women whose blood pressures were ≥ 140 mmHg (aOR, 4.26; 95% CI, 1.96-9.24), but the association between blood pressures of 130-139 mmHg and hypertension was not significant (aOR, 1.72; 95% CI, 0.95-3.11); however, a significant positive trend (p < 0.001) between increasing blood pressure and hypertension was observed. CONCLUSIONS: Gestational glycosuria, proteinuria, and increased blood pressure were associated with the development of maternal chronic diseases. These standard and inexpensive assessments may improve lifelong health management in women.

Zoledronic Acid-Associated Fanconi Syndrome in Patients With Cancer.

Zoledronic acid (ZA) is an antiresorptive agent typically used for fracture prevention in postmenopausal osteoporosis, malignancy-associated metastatic bone lesions, and as a treatment for hypercalcemia. ZA is excreted almost entirely by the kidney; as a result, a reduction in renal clearance can lead to its accumulation and potential renal toxicity. Although uncommon, acute kidney injury (AKI) from intravenous bisphosphonates has been described, with different patterns including tubulointerstitial nephritis, acute tubular necrosis, as well as focal segmental glomerulosclerosis. Here we present 4 patients with an underlying malignancy who each developed evidence of generalized proximal tubular dysfunction, also known as Fanconi syndrome, approximately 1 week after receiving treatment with ZA. On presentation, all patients had AKI, low serum bicarbonate levels, abnormal urinary acidification, hypophosphatemia, hypokalemia, and increased urine amino acid excretion or renal glycosuria. Based on the temporal association between ZA infusion and the development of these electrolyte abnormalities, each case is highly suggestive of ZA-associated Fanconi syndrome. Due to the severity of presentation, all required discontinuation of ZA and ongoing electrolyte repletion. Nephrologists and oncologists should be aware of this complication and consider ZA as a possible trigger of new-onset Fanconi syndrome.

Clinical algorithms for the management of intrapartum maternal urine abnormalities.

AIM: To develop evidence-based clinical algorithms for management of common intrapartum urinary abnormalities. POPULATION: Women with singleton, term pregnancies in active labour and immediate postnatal period, at low risk of complications. SETTING: Healthcare facilities in low- and middle-income countries. SEARCH STRATEGY: A systematic search and review were conducted on the current guidelines from WHO, NICE, ACOG and RCOG. Additional search was done on PubMed and The Cochrane Database of Systematic Reviews up to May 2020. CASE SCENARIOS: Four common intrapartum urinary abnormalities were selected: proteinuria, ketonuria, glycosuria and oliguria. Using reagent strip testing, glycosuria was defined as ≥2+ on one occasion or of ≥1+ on two or more occasions. Proteinuria was defined as ≥2+ and presence of ketone indicated ketonuria. Oliguria was defined as hourly urine output ≤30 ml. Thorough initial assessment using history, physical examination and basic investigations helped differentiate most of the underlying causes, which include diabetes mellitus, dehydration, sepsis, pre-eclampsia, shock, anaemia, obstructed labour, underlying cardiac or renal problems. A clinical algorithm was developed for each urinary abnormality to facilitate intrapartum management and referral of complicated cases for specialised care. CONCLUSIONS: Four simple, user-friendly and evidence-based clinical algorithms were developed to enhance intrapartum care of commonly encountered maternal urine abnormalities. These algorithms may be used to support healthcare professionals in clinical decision-making when handling normal and potentially complicated labour, especially in low resource countries. TWEETABLE ABSTRACT: Evidence-based clinical algorithms developed to guide intrapartum management of commonly encountered urinary abnormalities.

Clinical features of pediatric renal glucosuria cases due to SLC5A2 gene variants.

BACKGROUND: Familial renal glycosuria (FRG) is a rare renal tubular disorder characterized by a variable loss of glucose in the urine despite normal blood glucose levels, which is seen in a condition in which other tubular functions are preserved. In this study, the molecular and clinical characteristics of pediatric FRG cases due to SLC5A2 gene variants were defined. METHODS: Demographic features, diagnostic tests, and molecular analyses of patients with a diagnosis of FRG cases due to SLC5A2 gene variants were retrospectively analyzed between 2016 and 2019. RESULTS: The data of 16 patients who were clinically and genetically diagnosed with FRG in a 4-year period were analyzed. Seven (44%) of the cases were female and 9 (56%) were male. The median age at diagnosis was 6 years old (2 months old to 17 years old). Neuromotor development was found to be appropriate for the age in each case. Systemic blood pressure was evaluated as normal. A homozygous pathogenic variant in the SLC5A2 gene was detected in 14 patients in the genetic examination. A heterozygous variant was detected in one patient. In the other patient, two different heterozygous pathological variants were found in the SLC5A2 gene. CONCLUSIONS: It was revealed that growth and development were normal in children with glucosuria due to variations in the SCL5A2 gene. Renal function tests and urinary amino acid excretion were also within normal values. In our case series, the most common genetic variation in the SCL5A2 gene was the A219T (c.655G>A) variant.

Exposure to Moderate Glycosuria Induces Virulence of Group B Streptococcus.

To explore whether glycosuria induces virulence of uropathogens, in turn facilitating urinary tract infection (UTI), we exposed group B Streptococcus (GBS) strain 10/84 to human urine plain or with 300 mg/dL glucose (mimicking moderate glycosuria). Exposure to moderate glycosuria significantly augmented bacterial growth, kidney bacterial burden in a mouse model of ascending UTI, and virulence characteristics and expression of corresponding genes. Exposure to glycosuria increased GBS adherence to human bladder epithelial cell line and expression of corresponding PI2a fimbrial gene, antimicrobial peptide LL-37 resistance and bacterial surface charge modulating dltA, and GBS hemolytic ability and expression of genes encoding pore-forming toxins.

"The Bitter Truth of Sugar"-Euglycemic Diabetic Ketoacidosis due to Sodium-glucose Cotransporter-2 Inhibitors: A Case Series.

Diabetic ketoacidosis (DKA) is an acute and major complication of diabetes mellitus (DM), both type I and type II. Biochemically, DKA consists of a triad of blood sugar levels greater than 250 mg/dL, ketonemia of greater than 3 mmol/L and/or significant ketonuria, and a blood pH less than 7.3 with an increased anion gap. Currently, the sodium-glucose cotransporter-2 inhibitors (SGLT-2i) are widely used in management of type II diabetes. There have been several reports of an association between euglycemic diabetic ketoacidosis (EuDKA) and SGLT-2i agents. We present three different patients who were on SGLT-2i therapy who developed recurrent EuDKA postprocedure or sepsis. We believe that prolonged treatment (5-6 days) with intravenous (IV) insulin with glucose until resolution of glycosuria can be considered as an inexpensive marker of resolution of EuDKA. Moreover, the recommended duration for discontinuation of these drugs prior to elective procedures should be longer than 3 days. How to cite this article: Shah M, Pathrose E, Bhagwat NM, Chandy D. "The Bitter Truth of Sugar"-Euglycemic Diabetic Ketoacidosis due to Sodium-glucose Cotransporter-2 Inhibitors: A Case Series. Indian J Crit Care Med 2022;26(1):123-126.

Bittersweet: infective complications of drug-induced glycosuria in patients with diabetes mellitus on SGLT2-inhibitors: two case reports.

BACKGROUND: Sodium-glucose co-transporter 2 (SGLT2) inhibitors are novel hypoglycemic agents which reduce reabsorption of glucose at the renal proximal tubule, resulting in significant glycosuria and increased risk of genital mycotic infections (GMI). These infections are typically not severe as reported in large systematic reviews and meta-analyses of the medications. These reviews have also demonstrated significant cardiovascular benefits through other mechanisms of action, making them attractive options for the management of Type 2 diabetes mellitus (T2DM). We present two cases with underlying abnormalities of the urogenital tract in which the GMI were complicated and necessitated cessation of the SGLT2 inhibitor. CASE PRESENTATIONS: Both cases are patients with T2DM on empagliflozin, an SGLT2 inhibitor. The first case is a 64 year old man with Candida albicans balanitis and candidemia who was found to have an obstructing renal calculus and prostatic abscess requiring operative management. The second case describes a 72 year old man with Candida glabrata candidemia who was found to have prostatomegaly, balanitis xerotica obliterans with significant urethral stricture and bladder diverticulae. His treatment was more complex due to fluconazole resistance and concerns about urinary tract penetration of other antifungals. Both patients recovered following prolonged courses of antifungal therapy and in both cases the SGLT2 inhibitor was ceased. CONCLUSIONS: Despite their cardiovascular benefits, SGLT2 inhibitors can be associated with complicated fungal infections including candidemia and patients with anatomical abnormalities of the urogenital tract may be more susceptible to these infections as demonstrated in these cases. Clinicians should be aware of their mechanism of action and associated risk of infection and prior to prescription, assessment of urogenital anatomical abnormalities should be performed to identify patients who may be at risk of complicated infection.

Factors that predict glycaemic response to sodium-glucose linked transporter (SGLT) inhibitors.

AIM: To determine the clinical and biochemical variables associated with change in HbA1c in patients with type 2 diabetes who start sodium-glucose linked transporter (SGLT) inhibitor therapy. METHODS: We performed a prospective cohort study (ACTRN12616000833460) of 48 adults (30 male, 18 female) with type 2 diabetes who attended a tertiary hospital diabetes clinic. Fasting serum and urine samples, collected during clinic visits prior to and at 1, 12 and 24 weeks after commencing SGLT inhibitor treatment, were analysed for HbA1c, electrolytes, urea, creatinine and glucose. RESULTS: After 12 weeks, SGLT inhibitor therapy was associated with respective median (97% CI) decreases in weight, blood pressure, HbA1c and urine albumin/creatinine ratio of 3.0 (1.7-3.4) kg, 8 (2-16)/4 (3-9) mmHg, 6 (3-14) mmol/mol and 0.69 (0.18-1.8) mg/mmol. These effects persisted to 24 weeks. Urinary frequency and genitourinary infection were common adverse effects. Baseline HbA1c and eGFR independently predicted ΔHbA1c at 12 weeks whereas only baseline HbA1c independently predicted ΔHbA1c at 24 weeks. Urinary fractional glucose excretion and change in fasting glucose 1 week after starting SGLT inhibitor did not contribute to prediction of glycaemic response. CONCLUSIONS: SGLT inhibitor therapy in a hospital clinic setting was associated with clinical improvements comparable to those observed in clinical trials but with higher incidence of genitourinary side-effects. Baseline HbA1c and eGFR, but not urine fractional glucose excretion, predicted glycaemic response.

Tubular Injury Causing Protracted Glycosuria Following Withdrawal of a Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor: A Possible Role in the Development of Protracted Hypoglycemia and Ketoacidosis.

We herein present the case of a 45-year-old diabetic woman who developed diabetic ketoacidosis following the administration of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor. The patient had been diagnosed with diabetes three years previously and was being treated with multiple daily injections of insulin. Metformin hydrochloride and dapagliflozin were added seven months and 11 months later, respectively. Her clinical course was uneventful until the onset of influenza. She then discontinued insulin and oral medications voluntarily. On arrival at the hospital, she was found to be in a state of ketoacidosis, and promptly received insulin and saline infusion. In retrospect, the initial amount of glucose infused was insufficient, and the hypoglycemia was thought to have been prolonged. This phenomenon may also have affected her long-term urinary glucose excretion. Her urinary L-type fatty acid-binding protein (L-FABP) level was found to be markedly elevated (48.8 µg/g·Cr, reference value < 8.4 µg/g·Cr) as was her urinary ß2-microglobulin level (9,230 µg/L, reference value < 230 µg/L). Patients with SGLT-2 inhibitor-associated diabetic ketoacidosis often exhibit protracted hyperglycosuria, in which acute proximal renal tubular dysfunction is considered to be etiologically implicated.

Non-diabetic glycosuria as a diagnostic clue for acute tubulointerstitial nephritis in patients with azotemia.

BACKGROUND: Glycosuria is one of the manifestations of acute tubulointerstitial nephritis (ATIN), but may also be observed in other renal diseases. In this study, we investigated the value of non-diabetic glycosuria as a diagnostic clue for ATIN. METHODS: We retrospectively reviewed the medical records of adult patients who underwent a kidney biopsy as an evaluation for serum creatinine > 1.4 mg/dL. Patients with proteinuria in the nephrotic range, diabetes mellitus, or transplanted kidney were excluded. The laboratory abnormalities suggestive of tubular injury were compared between 28 patients (14 men and 14 women, mean age 48.5 ± 14.1 years) with ATIN and 116 patients (76 men and 40 women, mean age 53.1 ± 15.0 years) with other diagnoses. RESULTS: In ATIN, glycosuria (≥ 1+ on dipstick; 68%) was more frequent than hypophosphatemia (18%), hypouricemia (18%), hypokalemia (18%), and tubular proteinuria (40%). In other diagnoses, glycosuria (≥ 1+) was detected in 7 (6%) patients; 6 of them had the histological diagnosis of antineutrophil cytoplasmic antibody-associated glomerulonephritis. The presence of glycosuria (≥ 1+) had 68% sensitivity and 94% specificity for ATIN, with the positive likelihood ratio of 11.24 and the negative likelihood ratio of 0.34. Pyuria and low total CO2 were equally and more sensitive (68% and 71%, respectively) than glycosuria (≥ 1+), but had no diagnostic value due to low specificities (58% and 60%, respectively). CONCLUSION: In non-diabetic, non-nephrotic patients undergoing a kidney biopsy for azotemia, 1+ or higher glycosuria, if present, was a good predictor of the diagnosis of ATIN.

Metabolic adaptability in liver and gastrocnemius muscle of mice following subacute lead toxicity.

Lead (Pb) is one of several environmental pollutants that adversely affect human health by producing toxicity at the tissue level. The aim of the study was to understand the effects of Pb on the metabolic profiles of liver and gastrocnemius muscle of mice in relation to carbohydrate and fat metabolisms. Swiss albino mice were chosen and divided into two groups, control and Pb-treated. The Pb-treated animals were exposed to Pb at a dose of 5 mg/kg body weight for 30 days orally, which resulted in hypoglycemia, glycosuria, and increased glycogenolysis in the liver and gastrocnemius muscle of treated mice. Pyruvic acid, the end product of glycolysis decreased in muscular tissue and increased in the liver. Additionally, the activity of G-6Pase was depressed in the liver, whereas lactate dehydrogenase activity was increased in skeletal muscle only. An adaptive mechanism was initiated by stimulating glycogenolytic and retarding glycolytic activity in the liver and also by alteration of liver and muscle pyruvate dehydrogenase activity along with increased activity of malate dehydrogenase in skeletal muscle. There was enhancement of succinate dehydrogenase and nicotinamide adenine dinucleotide phosphate oxidase activities in the studied tissues. Interestingly, cholesterol, high-density lipoprotein, and low-density lipoprotein levels were elevated, whereas those of triglycerides were decreased in Pb-treated mice serum. The activities of fatty acid synthase and glyceraldehyde 3 phosphate dehydrogenase were depressed in Pb-treated mice livers. Pb also significantly altered the morphological features of the liver, skeletal muscle, and pancreas. These data suggested that subacute Pb exposure was responsible for metabolic modulation in an adaptive fashion in the liver and skeletal muscle of mice.

Sodium-glucose cotransporter inhibitors and oxidative stress: An update.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are therapeutic agents that have been used recently to reduce tubular absorption of glucose, leading to enhanced glycosuria, resulting in the reduction of blood glucose and improved diabetes control. Recent data suggest that SGLT2 inhibitors have antioxidant properties that may be key to the reduction in cardiovascular death found in clinical trials. Oxidative stress is involved in the development and progression of atherosclerosis, as well as underlying diabetes complications, and may result from either increased free-radical production, a reduction in antioxidative capacity, or a combination of both. In this report, we have reviewed the recent evidence of the impact that SGLT2 inhibition may have on improved oxidative stress by either amelioration of free-radical generation or potentiation of cellular antioxidative capacity, and its importance in the prevention of cardiovascular and diabetes complications.

Renal injury in Seipin-deficient lipodystrophic mice and its reversal by adipose tissue transplantation or leptin administration alone: adipose tissue-kidney crosstalk.

Seipin deficiency is responsible for type 2 congenital generalized lipodystrophy with severe loss of adipose tissue (AT) and could lead to renal failure in humans. However, the effect of Seipin on renal function is poorly understood. Here we report that Seipin knockout (SKO) mice exhibited impaired renal function, enlarged glomerular and mesangial surface areas, renal depositions of lipid, and advanced glycation end products. Elevated glycosuria and increased electrolyte excretion were also detected. Relative renal gene expression in fatty acid oxidation and reabsorption pathways were impaired in SKO mice. Elevated glycosuria might be associated with reduced renal glucose transporter 2 levels. To improve renal function, AT transplantation or leptin administration alone was performed. Both treatments effectively ameliorated renal injury by improving all of the parameters that were measured in the kidney. The treatments also rescued insulin resistance and low plasma leptin levels in SKO mice. Our findings demonstrate for the first time that Seipin deficiency induces renal injury, which is closely related to glucolipotoxicity and impaired renal reabsorption in SKO mice, and is primarily caused by the loss of AT and especially the lack of leptin. AT transplantation and leptin administration are two effective treatments for renal injury in Seipin-deficient mice.-Liu, X.-J., Wu, X.-Y., Wang, H., Wang, S.-X., Kong, W., Zhang, L., Liu, G., Huang, W. Renal injury in Seipin-deficient lipodystrophic mice and its reversal by adipose tissue transplantation or leptin administration alone: adipose tissue-kidney crosstalk.

Glycosuria amount in response to hyperglycaemia and risk for diabetic kidney disease and related events in Type 1 diabetic patients.

BACKGROUND: Hyperglycaemia impairs tubulo-glomerular feedback. We tested whether variable tubulo-glomerular feedback during hyperglycaemia contributes to renal risk heterogeneity seen in Type 1 diabetes. METHODS: During the period 1990-92, we studied the tubulo-glomerular feedback in Type 1 diabetic patients at high or low renal risk [21 of 54 with glomerular hyperfiltration and/or microalbuminuria against 11 of 55 with normal glomerular filtration rate (GFR) and urinary albumin despite uncontrolled diabetes]. The GFR, effective renal plasma flow, mean arterial pressure and fractional reabsorptions of glucose, osmols, sodium and lithium were measured sequentially during normo- and hyperglycaemia. All patients were followed up until 2016 for incident proteinuria, estimated GFR <60 mL/min/1.73 m2, doubling of serum creatinine, end-stage renal disease or all-cause death. RESULTS: Glycaemia increased from 6.1 ± 1.3 to 15.1 ± 1.9 mmol/L in both high-risk and low-risk patients. Glycosuria was lower in the high- versus low-risk patients: 0.34 ± 0.25 versus 0.64 ± 0.44 mmol/min (P = 0.03). Both groups displayed similar kidney function during normoglycaemia. Hyperglycaemia increased more importantly GFR and fractional reabsorptions, and pre-glomerular vasodilatation in the high- than in the low-risk patients (all P < 0.05). Over 21 years, 31.5% high- versus 12.7% low-risk patients developed endpoints (adjusted P = 0.006). In a multi-adjusted survival analysis of patients having undergone renal tests, each 0.10 mmol/min glycosuria during hyperglycaemia reduced the outcome risk by 0.72 (95% confidence interval 0.49-0.97, P = 0.03). CONCLUSIONS: Reduced tubulo-glomerular feedback and glycosuria during hyperglycaemia indicate high renal risk for Type 1 diabetic patients. Inter-individual variability in tubulo-glomerular feedback activity determines renal risk in Type 1 diabetes.

A Pediatric Case of Graves' Hyperthyroidism with Associated Glucose Intolerance Detected by a Urine Glucose Screening Program at School.

We report here a 13-year-old female with Graves' disease, whose diagnostic clue was glycosuria, which was detected by a urine glucose screening program at school. She had had mild general malaise, and a physical examination revealed a slightly enlarged thyroid gland. Hyperthyroidism (thyroid-stimulating hormone (TSH) < 0.01 µU/ml, free triiodothyronine (fT3) 23.57 pg/ml, free thyroxine (fT4) 3.38 ng/dl) and anti-thyroid autoantibodies (TRAb 43.6%) were detected in laboratory tests, and her plasma glucose at 120 minutes was 142 mg/dl in a 75 g oral glucose tolerance test. She was diagnosed as having borderline diabetes. These findings revealed a diagnosis of Graves' hyperthyroidism with associated impaired glucose tolerance. Although it is reported that many adults with hyperthyroidism develop disorders of glucose metabolism, pediatric patients rarely have complications of glucose intolerance or diabetes mellitus, and there are no previous reports of Graves' disease diagnosed by a urine glucose screening program at school. This case suggests a possibility of abnormalities in glucose metabolism even in pediatric cases of Graves' disease. To avoid overlooking the diagnosis of glucose intolerance associated with hyperthyroidism, a careful medical interview and examination should be performed even if the clinical features are mild.

Metabolic consequences of acute and chronic empagliflozin administration in treatment-naive and metformin pretreated patients with type 2 diabetes.

AIMS/HYPOTHESIS: Sodium glucose co-transporter 2 (SGLT2) inhibitors lower glycaemia by inducing glycosuria, but raise endogenous glucose production (EGP). Metformin lowers glycaemia mainly by suppressing EGP. We compared the effects of the SGLT2 inhibitor empagliflozin in treatment-naive (TN) and metformin pretreated (Met) patients with type 2 diabetes. METHODS: A total of 32 TN and 34 patients on a stable dose of metformin, two subgroups of a study that we previously reported, received a mixed meal with double-tracer glucose administration and indirect calorimetry at baseline, after a single 25 mg dose of empagliflozin, and after 4 weeks of treatment with empagliflozin 25 mg/day. RESULTS: At baseline, compared with the TN group, the Met group had higher fasting glycaemia (9.1 ± 1.7 vs 8.2 ± 1.3 mmol/l), lower fasting and postmeal insulin secretion, lower beta cell glucose sensitivity (37 [18] vs 58 [43] pmol min(-1) m(-2) [mmol/l](-1), median [interquartile range]) and insulin:glucagon ratio, and higher fasting EGP (15.9 [4.3] vs 12.1 [2.7] µmol kgFFM (-1) min(-1)). Change from baseline in fasting EGP after single dose and 4 weeks of treatment with empagliflozin was similar in the Met and TN groups (19.6 [4.2] and 19.0 [2.3] in Met vs 16.2 [3.6] and 15.5 [3.2] µmol kgFFM (-1) min(-1) in TN for acute and chronic dosing, respectively). Beta cell glucose sensitivity increased less in Met than TN patients, whereas substrate utilisation shifted from carbohydrate to fat more in Met than TN patients. CONCLUSIONS/INTERPRETATION: At baseline, Met patients with type 2 diabetes had more advanced disease than TN patients, featuring worse beta cell function and higher EGP. Empagliflozin induced similar glycosuria and metabolic and hormonal responses in Met and TN patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01248364; European Union Clinical Trials Register 2010-018708-99.