Glucose Lowering Efficacy and Pleiotropic Effects of Sodium-Glucose Cotransporter 2 Inhibitors.

In type 2 diabetes, the maladaptive upregulation of sodium-glucose cotransporter 2 (SGLT2) protein expression and activity contribute to the maintenance of hyperglycemia. By inhibiting these proteins, SGLT2 inhibitors increase urinary glucose excretion (UGE) that leads to fall in plasma glucose concentrations and improvement in all glycemic parameters. Clinical studies have demonstrated that in patients with type 2 diabetes, SGLT2 inhibitors resulted in sustained reductions in glycated hemoglobin (HbA1C), body weight, blood pressure and serum uric acid levels. Interestingly, the cardiovascular (CV) and renal outcome trials revealed the beneficial effects of SGLT2 inhibitors on CV and renal functions. Because the benefits were seen soon after initiation of SGLT2 inhibitors, these observations are explained by effects beyond their glucose lowering capacity. SGLT2 inhibitors also reduce liver fat in patients with nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes. This chapter describes the basic information about SGLT2 inhibitors, current status of SGLT2 inhibitors in the management of type 2 diabetes and their beneficial effects in addition to glycemic control.

Effect of Empagliflozin on Liver Fat in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial (E-LIFT Trial).

OBJECTIVE: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors have been shown to reduce liver fat in rodent models. Data regarding the effect of SGLT-2 inhibitors on human liver fat are scarce. This study examined the effect of empagliflozin (an SGLT-2 inhibitor) on liver fat in patients with type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) by using MRI-derived proton density fat fraction (MRI-PDFF). RESEARCH DESIGN AND METHODS: Fifty patients with type 2 diabetes and NAFLD were randomly assigned to either the empagliflozin group (standard treatment for type 2 diabetes plus empagliflozin 10 mg daily) or the control group (standard treatment without empagliflozin) for 20 weeks. Change in liver fat was measured by MRI-PDFF. Secondary outcome measures were change in alanine transaminase (ALT), aspartate transaminase (AST), and γ-glutamyl transferase (GGT) levels. RESULTS: When included in the standard treatment for type 2 diabetes, empagliflozin was significantly better at reducing liver fat (mean MRI-PDFF difference between the empagliflozin and control groups -4.0%; P < 0.0001). Compared with baseline, significant reduction was found in the end-of-treatment MRI-PDFF for the empagliflozin group (16.2% to 11.3%; P < 0.0001) and a nonsignificant change was found in the control group (16.4% to 15.5%; P = 0.057). The two groups showed a significant difference for change in serum ALT level (P = 0.005) and nonsignificant differences for AST (P = 0.212) and GGT (P = 0.057) levels. CONCLUSIONS: When included in the standard treatment for type 2 diabetes, empagliflozin reduces liver fat and improves ALT levels in patients with type 2 diabetes and NAFLD.

Acute severe diarrhoea and hyponatremia after zoledronic acid infusion: an acute phase reaction.

Zoledronic acid (ZA), an intravenous aminobisphosphonate, is prescribed widely for postmenopausal osteoporosis. It is a relatively safe drug but may cause adverse effects including acute phase reaction. Oral non-aminobisphosphonates are known to cause diarrhoea that is usually mild and self-limited. Intravenous amino-bisphosphonates are not known to cause diarrhoea. We describe a case of acute watery diarrhoea complicated by severe hyponatremia and hypotension following ZA infusion. The patient needed intensive care for four days. To the best of our knowledge, this type of acute diarrhoea complicated by severe hyponatremia, following ZA infusion, is not reported so far. Strong temporal relation with ZA administration makes it the most likely cause. Furthermore, all laboratory and imaging parameters indicate that the secretory diarrhoea may be a component of acute phase reaction. According to World Health Organization (WHO) causality scale, ZA was a probable cause of acute watery diarrhoea in our patient. Clinicians should be aware that ZA administration can cause acute watery diarrhoea and may lead to severe hypotension and hyponatremia.

Glucocorticoid sparing effect of zoledronic acid in sarcoid hypercalcemia.

INTRODUCTION: Glucocorticoids are regarded as first-line therapy in the management of hypercalcemia associated with sarcoidosis. However, prolonged glucocorticoid therapy leads to metabolic abnormalities, Cushingoid habitus, and impairment of bone health. This study demonstrates the efficacy and glucocorticoid-sparing effect of zoledronic acid in sarcoid hypercalcemia. METHODS: We present three patients with sarcoid hypercalcemia. They were successfully managed with oral glucocorticoids for many months. However, all patients developed adverse effects of glucocorticoids. When tapering of glucocorticoids was attempted, hypercalcemia recurred. Zoledronic acid was administered in order to control hypercalcemia and to allow tapering of glucocorticoids. RESULTS: Following zoledronic acid administration, serum calcium level normalised and glucocorticoids could be discontinued in all the three patients. Normocalcemia was maintained for an average of 18 months after a single infusion. Sarcoidosis remained in remission in all the three patients. CONCLUSION: Zoledronic acid should be studied as a potential first-line agent for sarcoid hypercalcemia. Furthermore, disease-modifying effects of zoledronic acid in sarcoidosis should be investigated.

Hypercalcemia of advanced chronic liver disease: a forgotten clinical entity!

Hypercalcemia caused by advanced chronic liver disease (CLD) without hepatic neoplasia is uncommonly reported and poorly understood condition. We are reporting two cases of advanced CLD who developed hypercalcemia in the course of the disease. This diagnosis of exclusion was made only after meticulous ruling out of all causes of hypercalcemia. The unique feature of this type of hypercalcemia is its transient nature that may or may not require treatment. This clinical condition in patients with CLD should be kept in mind while evaluating the cause of hypercalcemia in them.

Dissociated hypopituitarism after spontaneous pituitary apoplexy in acromegaly.

INTRODUCTION: Pituitary apoplexy is an uncommon event and usually occurs in non-functioning pituitary tumors. Among the functioning tumors, prolactinomas are the ones most likely to apoplexy. Apoplexy in growth hormone (GH) producing adenomas is a very rare event with less than thirty cases reported worldwide. OBJECTIVE: To describe a case of spontaneous pituitary apoplexy in acromegaly. CASE REPORT: A 55 year old smoker male presented to the our outpatient clinic in 2004 with complaints of gradual onset increase in the size of hands and feet, bilateral knee pain, increased sweating and blurring of vision. Investigations uncovered diabetes mellitus by a casual blood glucose of 243 mg/dl and HbA1c of 8.5%. Growth hormone suppression test using 75 gram oral glucose showed a 60 minute growth hormone of 105 ng/ml. Magnetic resonance imaging of the sellar region showed a 12.0 mm × 10.0 mm pituitary adenoma. The patient was planned for transsphenoidal tumor decompression. However, the patient was lost to follow up. Eight-years later, he presented in the emergency department of our institute with sudden onset headache, vomiting and decreased level of consciousness of one day duration. CT scan of the head with focus on the sella was suggestive of apoplexy which was later confirmed by the MRI of the sellar region. CONCLUSION: Although acromegaly can remit following apoplexy of the responsible pituitary adenoma, long term follow up is needed for early detection of the development of deficiency of pituitary hormones which may occur over years following the event as well as to detect tumor regrowth which again may occur several years later.

Deep vein thrombosis in a patient of Sheehan's syndrome: Autoimmunity or hypercoagulabilty.

INTRODUCTION: Literature is inconsistent whether patients with hypopituitarism have increased risk of thrombosis. Recent data has shown problems with the coagulation system in Sheehan's syndrome (SS). Here, we describe a case of SS which presented with deep vein thrombosis. OBJECTIVE: To describe a case of SS presenting as deep vein thrombosis. CASE REPORT: A 30-year-old female was admitted to the general medicine ward with 1 month history of gradual onset swelling and pain in the left leg. The left calf diameter was 5 cm greater than the right. Doppler of the lower limbs revealed thrombosis in the left popliteal vein. Patient's coagulation profile revealed a normal prothrombin time of 12 sec, activated partial thromboplastin time of 30 sec, positive D-dimer, negative protein C and protein S and normal titres of antinuclear antibodies. Echocardiography showed an ejection fraction of 52 percent. Endocrinology consultation was sought in view of clinical suspicion of hypothyroidism. Endocrinology review revealed a significant past history of primary postpartum hemorrhage, lactation failure and secondary amenorrhea since the delivery of the last child 6 years back. She had clinical features of growth hormone, thyroid hormone and adrenocorticotropic hormone deficiency. Hormonal analysis showed features of central hypothyroidism, secondary adrenal insufficiency and growth hormone deficiency which was subsequently confirmed by insulin tolerance test. CONCLUSION: SS patients may have increased risk of thrombosis.

Autoimmune polyglandular syndrome type 1 with reversible dilated cardiomyopathy: complete recovery after correction of hypocalcemia and hypocortisolemia.

Autoimmune polyglandular syndrome type 1 (APS1) - characterized by the triad of mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency - is an uncommon entity. In this case report we describe the case of a young girl who presented with classic features of APS1 and dilated cardiomyopathy, which were missed during her presentation to the children's hospital. Her condition improved only when appropriate replacement therapy in the form of calcium, calcitriol and hydrocortisone was instituted. Hypocalcemia and hypocortisol state are curable causes of myocardial dysfunction and subsequent congestive cardiac failure, and should always be considered in the differential diagnosis of resistant congestive cardiac failure, especially in children. To the best of our knowledge, cardiomyopathy in the setting of APS1 has never been described previously and can remain unrecognized for a long time and present with life threatening complications.

Pattern of urinary albumin excretion in normotensive young and adolescent Indian women with polycystic ovary syndrome.

OBJECTIVE: Polycystic ovarian syndrome (PCOS) is a clinically heterogeneous endocrine disorder affecting up to 4-8% of women of reproductive age. The aim of this study was to evaluate the presence of microalbuminuria in women with PCOS and study its correlation with the various metabolic, clinical, and hormonal parameters. MATERIALS AND METHODS: A cross-sectional study involving 69 PCOS women was carried out in a tertiary care center hospital. The diagnosis of PCOS was made according to the Rotterdam criteria. Blood samples were collected in the follicular phase of the menstrual cycle and analyzed for fasting luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin (PRL), 17-hydroxyprogesterone (17-OHP), total testosterone (T), glucose, insulin, and lipid profile. Urinary albumin was measured in the first void spot urine sample. RESULTS: The mean age of the subjects was 22.0 ± 4.1 years and 21.8 ± 4.7 years in normoalbuminuric and microalbuminuric groups, respectively. Urinary albumin excretion (UAE) varied from 5 mg/l to 100 mg/ml, with a median of 5 mg/l. Microalbuminuria was observed in 17/69 (24.6%) of subjects. The mean UAE was 3.65 ± 4.44 mg/l in the normoalbuminuria group versus 45.29 ± 22.74 mg/l in the microalbuminuria group. Upon univariate analysis, hip circumference, diastolic blood pressure, and fasting blood glucose showed significant correlations with urinary albumin concentration (r = 0.264, 0.264, and 0.551, respectively; P = 0.028, 0.029, and 0.000, respectively). No association between UAE and the usual cardiovascular risk factors could be found upon regression analysis. CONCLUSION: About 24.6% of women with PCOS showed presence of microalbuminuria in the first void spot urine sample. Screening for the presence of microalbuminuria can help in early identification of a subset of PCOS women with a high risk for future CVD, who can be subjected to preventive strategies at the earliest. However, further studies are needed before recommending routine use of UAE in PCOS cases for the detection of CVD risk.

Detection of autoantibodies against glycosylated-DNA in diabetic subjects: Its possible correlation with HbA(1C).

AIMS: The vascular tissues have a long memory of their previous glycemic control and intervention studies have demonstrated that microvascular complications are highly correlated with mean glycemic control as measured by glycolated hemoglobin A1C ( HbA1c)The present study was carried out to evaluate the autoantibodies against glycosylated DNA (DNA-AGEs) in diabetic sera to see if the level of HbA1c has correlation with the activity of DNA-AGEs, another marker of chronic glycemia. METHODS: Glucose-6-phosphate induced glycosylation of native DNA was studied in 150 diabetic sera (T1DM=9, T2DM=141) by spectroscopic techniques (UV and fluorescence) and agarose gel electrophoresis. Direct binding and inhibition enzyme immunoassays were carried out to evaluate binding and specificity of anti-glycated-DNA autoantibodies (anti-DNA-AGE autoantibodies) in sera of diabetes patients. A quantitative estimation of HbA1c was carried out in normal and diabetes sera. RESULTS: Anti-DNA-AGEs autoantibodies in 55% of diabetic sera (85/150) showed more binding with glycated-DNA compared to native DNA which was subjected to inhibition ELISA indicating true interaction of these autoantibodies in diabetes with glycated DNA. Higher binding with glycosylated-DNA against native-DNA was observed in subjects with HbA1c of 9.8 ± 3.3% compared to those with HbA1c of 7.7 ± 1.7% (p< 0.001). Linear correlation analysis showed that mean absorbance difference was significantly related to HbA1c (r=0.486, p< 0.001), nephropathy (r= 0.239, p< 0.003), retinopathy (r=0.165, p< 0.05). CONCLUSIONS: Autoantibodies against glycosylated DNA were correlated with HbA1c and microvascular complications and may be useful as another biomarker for assessment of chronic glycemia.