Indian Expert Review on Use of Teneligliptin in patients with Diabetes and its Safety and Efficacy (INTENSE).

INTRODUCTION: Management of diabetes in India remains less than satisfactory despite a huge prevalence of type 2 diabetes (T2D). Associated obesity, inadequate lifestyle modifications and burden of treatment costs are certain major issues contributing to inadequate management of diabetes in India. AIM: To evaluate the use of Teneligliptin in patients with diabetes and its safety, efficacy and cost effectiveness especially in Indian patients with T2D. METHODS: A detailed analysis of the best available scientific evidence (clinical trials, meta-analyses and real-world experience) was performed to create an evidence driven understanding of teneligliptin's efficacy, safety and cost effectiveness. Fourteen leading endocrinologists contributed as experts and the modified Delphi process was followed. Evidences and clinical questions were discussed over a series of web and in a live meeting. Final draft was created based on the opinions endorsed by the experts. RESULTS: Teneligliptin is the most commonly used gliptin in India and exhibits pharmacokinetic and pharmacodynamic advantages as well as greater cost effectiveness compared to other gliptins. It has been recognized as an efficacious and well tolerated antidiabetic agent both as monotherapy and in combination based on multiple clinical trials, meta-analyses and real world studies. Teneligliptin as add on therapy to other antidiabetic drugs (OADs) or insulin has provided significant reductions in HbA1c, fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) levels and is generally well tolerated with low risk of hypoglycemia both in short term and long term. Studies have also proven its efficacy in ameliorating glucose fluctuations, reducing post prandial insulin requirement, increasing active incretin levels and improving pancreatic ß cells function. Efficacy and safety has also been proven in all age groups, all stages of renal disease and mild to moderate hepatic disease. QT prolongation is not seen even with maximum recommended dose of 40 mg/day. CONCLUSION: Teneligliptin has firmly positioned itself as a very important drug in the armamentarium for managing T2D. It offers efficacy, safety and cost-effective therapeutic choice in Indian patients with T2D.

Can the 128-Hz tuning fork be an alternative to the biothesiometer for diabetic peripheral neuropathy screening? A cross-sectional study in a tertiary hospital in East India.

INTRODUCTION: Diabetic neuropathy is frequently underdiagnosed and undertreated. Logistic problems accompany the routine use of the biothesiometer. Hence, we attempted to find a more easily available alternative. RESEARCH DESIGN AND METHODS: 149 patients with diabetes visiting the outpatient endocrinology clinic were assessed for vibration sense using a 128-Hz tuning fork (absolute timing method) and a biothesiometer. A reading of >25 V on the biothesiometer (known as vibration perception threshold or VPT) was taken as the diagnostic criterion for severe neuropathy while >15 V was used as an indicator of the mild form. The sensitivity and specificity were calculated by constructing the receiver operating characteristic curve (ROC). A p value of <0.05 was considered as statistically significant. RESULTS: The timed tuning fork (TTF) test showed a statistically significant correlation with the VPT measurements (r=-0.5, p=0.000). Using the VPT findings as a reference, a timed tuning fork cut-off of 4.8 s was 76% sensitive and 77% specific in diagnosing mild neuropathy while absent tuning fork sensation demonstrated 70% sensitivity and 90% specificity in detecting severe neuropathy. CONCLUSIONS: The tuning fork test demonstrated significant sensitivity and specificity in diagnosing diabetic peripheral neuropathy when compared against the biothesiometer. A cut-off of 4.8 s can be a useful indicator of the early stages of onset of the condition.

Rare coexistence of hypopituitarism with osteogenesis imperfecta - A double-trouble for bone.

Osteogenesis imperfecta (OI) commonly involving defects in COL1A1 and COL1A2 is a rare hereditary disease of bone fragility affecting 6-7 per 100,000 population. On the other hand, hypopituitarism is a separate entity that manifests with reduced levels of pituitary hormones. The cooccurrence of these two is seldom reported previously in literature as a deviation from Occam's razor. Here, we reported a case of pathological fracture in a 31-year-old male who had blue sclera and secondary adrenal insufficiency, hypogonadotropic hypogonadism, and growth hormone deficiency along with primary autoimmune hypothyroidism. Diagnosis of OI was suggested by heterozygous missense variant in exon 40 of the COL1A2 gene (chr7: g.94423092G > A; Depth: 99×) that resulted in the amino acid substitution of Serine for Glycine at codon 847. Replacement of glucocorticoid, levothyroxine, and testosterone was started along with antiresorptive therapy for better bone health outcomes.

Swyer Syndrome Presenting as Dysgerminoma: A Case Report.

Complete gonadal dysgenesis with 46,XY karyotype is a clinical condition characterized by the absence of testicular tissue but with the presence of typical Müllerian structures in a phenotypically female individual. The condition presents as primary amenorrhoea or delayed puberty. Eventually, malignant neoplasms may arise. We report a case of a 16-year-old Indian male with Swyer syndrome presenting with primary amenorrhoea and with an earlier diagnosis of a malignant dysgerminoma in the right ovary.

Laron Syndrome: A Tale of Two Siblings.

Primary growth hormone (GH) resistance or growth hormone insensitivity syndrome, also called Laron syndrome, is a hereditary disease caused by mutations in the GH receptor or in the post-receptor signaling pathway. This disorder is characterized by postnatal growth failure resembling GH deficiency. Differentiating the two conditions is necessary. We present the cases of two siblings, a 16-year-old female and a 9-year-old male, born from a consanguineous union. Both had normal birth weights with subsequent severe short stature and delayed teeth eruption, with no features suggestive of any systemic illness. Serum insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) were both low. Suspecting GH deficiency, provocative testing with clonidine was done revealing peak growth hormone >40 ng/mL in both patients. In view of low IGF1 and IGFBP3 and high GH on stimulation, IGF1 generation test was done for both siblings, with values supporting the diagnosis of GH insensitivity or Laron syndrome.

Diagnostic approach in 46, XY DSD: an endocrine society of bengal (ESB) consensus statement.

OBJECTIVES: 46, XY difference/disorder of sex development (DSD) is a relatively uncommon group of heterogeneous disorders with varying degree of underandrogenization of male genitalia. Such patients should be approached systematically to reach an aetiological diagnosis. However, we lack, at present, a clinical practice guideline on diagnostic approach in 46, XY DSD from this part of the globe. Moreover, debate persists regarding the timing and cut-offs of different hormonal tests, performed in these cases. The consensus committee consisting of 34 highly experienced endocrinologists with interest and experience in managing DSD discussed and drafted a consensus statement on the diagnostic approach to 46, XY DSD focussing on relevant history, clinical examination, biochemical evaluation, imaging and genetic analysis. CONTENT: The consensus was guided by systematic reviews of existing literature followed by discussion. An initial draft was prepared and distributed among the members. The members provided their scientific inputs, and all the relevant suggestions were incorporated. The final draft was approved by the committee members. SUMMARY: The diagnostic approach in 46, XY DSD should be multidisciplinary although coordinated by an experienced endocrinologist. We recommend formal Karyotyping, even if Y chromosome material has been detected by other methods. Meticulous history taking and thorough head-to-toe examination should initially be performed with focus on external genitalia, including location of gonads. Decision regarding hormonal and other biochemical investigations should be made according to the age and interpreted according to age-appropriate norms Although LC-MS/MS is the preferred mode of steroid hormone measurements, immunoassays, which are widely available and less expensive, are acceptable alternatives. All patients with 46, XY DSD should undergo abdominopelvic ultrasonography by a trained radiologist. MRI of the abdomen and/or laparoscopy may be used to demonstrate the Mullerian structure and/or to localize the gonads. Genetic studies, which include copy number variation (CNV) or molecular testing of a candidate gene or next generation sequencing then should be ordered in a stepwise manner depending on the clinical, biochemical, hormonal, and radiological findings. OUTLOOK: The members of the committee believe that patients with 46, XY DSD need to be approached systematically. The proposed diagnostic algorithm, provided in the consensus statement, is cost effective and when supplemented with appropriate genetic studies, may help to reach an aetiological diagnosis in majority of such cases.

Effects of Hydroxychloroquine on Progression of Diabetic Retinopathy in Subjects with Rheumatoid Arthritis and Type 2 Diabetes Mellitus.

OBJECTIVE: The study was conducted to investigate the effects of hydroxychloroquine, an anti-inflammatory drug, which was recently approved and used as an add on oral antidiabetic drug for uncontrolled Type 2 Diabetes Mellitus (DM) on an adequate dose of sulfonylurea and metformin on the progression of diabetic retinopathy (DR) in subjects with Rheumatoid Arthritis and Type 2 Diabetes Mellitus. The primary objective was to evaluate the effect of hydroxychloroquine on the onset of Diabetic Retinopathy (DR) and progression of the disease. Best-corrected visual acuity (BCVA) charts with 3 or more lines worsening of visual acuity and the development of clinically significant macular edema (CSME) were added as secondary objectives as described in the Early Treatment Diabetic Retinopathy Study (ETDRS). METHODS: This retrospective analysis was done from medical records of all Rheumatoid Arthritis (RA) patients who also had T2DM and were treated with hydroxychloroquine (HCQ) 400 mg OD or 200 mg BID (N=65) and received ophthalmologic care at an endocrinology clinic in India up to a mean follow-up of 3.5±0.5 years and matched subjects taking any other disease-modifying antirheumatic drugs (DMARD) and pioglitazone (N=34). RESULTS: Baseline characteristics were similar in both the groups, with matched glycated haemoglobin (9.1 % and 9.2 % respectively, p=0.127). In both groups, over 3.5 years, HbA1c was reduced significantly. No new cases of DR were detected in the HCQ group, whereas 2 patients had developed DR in the pioglitazone group. At the base line visit, mild non-proliferative Diabetic Retinopathy (NPDR) was present in 18 eyes and 14 eyes in the HCQ and pioglitazone groups, respectively. Progression to moderate NPDR over 3.5 years occurred in 2 out of 18 (11 %) eyes in the HCQ group and 8 out of 14 (57 %) eyes in the pioglitazone group, respectively, representing a significant relative risk reduction (p=.001). No patients had progressed from mild NPDR to severe NPDR in the HCQ group, whereas 2 eyes had progressed from mild NPDR to severe NPDR in the pioglitazone group. None of the patients in either arm developed diabetic macular oedema. CONCLUSION: Progression of DR from mild to moderate NPDR or severe NPDR may be delayed by HCQ. Large scale randomised prospective clinical trial is required to establish the risk-benefit profiles of HCQ in T2DM.ct.

A Novel Homozygous CYP19A1 Gene Mutation Causing Aromatase Deficiency.

Aromatase deficiency is a rare autosomal recessive disorder and its exact prevalence is not known. Aromatase enzyme catalyzes the conversion of androgens to estrogens in gonadal and extra-gonadal tissues. Deficiency of aromatase enzyme can lead to ambiguous genitalia in a female child and maternal virilization during pregnancy due to raised androgen levels in the mother. A 10-month-old child was referred to our outpatient department for the evaluation of ambiguous genitalia. There was a history of maternal virilization during pregnancy. Karyotype of the child was 46XX. Congenital adrenal hyperplasia was ruled out as serum cortisol, plasma adrenocorticotropic hormone, and 17-hydroxyprogesterone were within normal limits. Hormonal assays showed elevated follicle-stimulating hormone and luteinizing hormone, with raised testosterone and low estradiol levels. Based on these findings, aromatase deficiency was suspected. A novel homozygous mutation c.1376delA located on exon 10 was identified on the CYP19A1 gene. We identified a novel mutation in the CYP19A1 gene in a patient who presented with ambiguous genitalia and maternal virilization during pregnancy.

Transformation of Peripheral Sexual Precocity to Central Sexual Precocity Following Treatment of Granulosa Cell Tumor of the Ovary.

Juvenile granulosa cell tumor leading to isosexual peripheral precocious puberty is a well-known association. Here, we report a rare case of central precocious puberty secondary to granulosa cell tumor of the ovary. A five-year and five-month-old girl presented with a history of progressive enlargement of bilateral breasts and intermittent vaginal spotting, associated with growth acceleration. Elevated estradiol and suppressed serum follicle-stimulating hormone were found on investigation. Additionally, abdominal and pelvic ultrasonography was suggestive of a right ovarian mass, which proved to be a juvenile granulosa cell tumor on histopathology and immunohistochemistry, leading to a diagnosis of peripheral precocious puberty secondary to granulosa cell tumor of the ovary. One and a half years after resection of the tumor, secondary sexual characteristics progressed with regression of tumor markers, and no mass was noted on ultrasonography, leading to the suspicion of central precocious puberty. Pubertal basal luteinizing hormone (LH) and elevated triptorelin-stimulated LH confirmed the diagnosis of central precocious puberty secondary to granulosa cell tumor of the ovary.

Absence of Vitamin D Deficiency Among Outdoor Workers With Type 2 Diabetes Mellitus in Southern West Bengal, India.

BACKGROUND: Vitamin D deficiency is widespread globally and is associated with type 2 diabetes mellitus (T2DM). Studies suggest markedly lower prevalence of vitamin D deficiency in outdoor workers compared to indoor workers. However, data on the vitamin D status of outdoor workers with T2DM is lacking. AIMS: We assessed the vitamin D status of outdoor workers with T2DM residing across several districts of Southern West Bengal, India. DESIGN: The present study is a descriptive observational study. MATERIAL AND METHODS: A total of 128 outdoor workers with T2DM were assessed for serum 25-hydroxyvitamin D (25(OH)D) during December 2019 after excluding common confounders except sun exposure (which was detailed using a questionnaire). Hospital staff were indoor controls, and vitamin D status was classified as per the Institute of Medicine guidelines. RESULTS: The mean serum 25(OH)D of outdoor workers with T2DM was 21.79 ± 6.31 ng/mL, with only 2.34% (n = 3) having vitamin D deficiency and 57.03% (n = 73) having sufficient serum 25(OH)D levels. The mean serum 25(OH)D of indoor controls was significantly lower at 16.67 ± 9.82 ng/mL (p = 0.003), with 33.33% being vitamin D deficient. Serum 25(OH)D in outdoor workers with T2DM did not have a significant correlation with indices of sun exposure. CONCLUSIONS: Vitamin D deficiency is practically absent in outdoor workers with T2DM residing in Southern West Bengal, India.

A Case of Elephantiasic Pretibial Myxedema Successfully Treated With Intralesional Triamcinolone Acetate.

Graves' dermopathy is one of the extra-thyroidal manifestations of Graves' disease (GD) and is characterized by the accumulation of glycosaminoglycans in the reticular dermis. In the majority of cases, pretibial myxedema is self-limiting but, in some cases, it can lead to structural and functional damage. Topical steroids with occlusive dressing remain the conventional treatment, but intralesional steroids have shown promising results. We hereby present a case of pretibial myxedema treated successfully with intralesional triamcinolone acetate.

Diabetes and COVID-19: A Review.

Coronavirus Disease 2019 (COVID-19) is an emerging disease and since its first identification in Wuhan, China, in December 2019, there has been a rapid increase in cases and deaths across the world. COVID-19 has been shown to have an immense impact in infected persons with diabetes, worsening their outcome, especially in elderly, smokers, obese, those having CVD, CKD, poor glycemic control and long duration of diabetes. In this review we summarize the current understanding of `the impact of COVID-19 on diabetes and discusses the pathophysiological mechanisms and management of diabetes and its complication in this scenario.

Kidney Disease in Type 2 Diabetes Mellitus and Benefits of Sodium-Glucose Cotransporter 2 Inhibitors: A Consensus Statement.

Diabetic kidney disease (DKD) occurs in approximately 20-40% of patients with type 2 diabetes mellitus. Patients with DKD have a higher risk of cardiovascular and all-cause mortality. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and antihyperglycemic drugs form the mainstay of DKD management and aim to restrict progression to more severe stages of DKD. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) control hyperglycemia by blocking renal glucose reabsorption in addition to preventing inflammation, thereby improving endothelial function and reducing oxidative stress; consequently, this class of prescription medicines is emerging as an important addition to the therapeutic armamentarium. The EMPA-REG OUTCOME, DECLARE TIMI 58, and CANVAS trials demonstrated the renoprotective effects of SGLT2i, such as restricting decline in glomerular filtration rate, in the progression of albuminuria, and in death due to renal causes. The renoprotection provided by SGLT2i was further confirmed in the CREDENCE study, which showed a 30% reduction in progression of chronic kidney disease, and in the DELIGHT study, which demonstrated a reduction in albuminuria with dapagliflozin compared with placebo (- 21.0%, confidence interval [CI] - 34.1 to - 5.2, p = 0.011). Furthermore, a meta-analysis demonstrated a reduced risk of dialysis, transplantation, or death due to kidney disease (relative risk 0.67; 95% CI 0.52-0.86; p = 0.0019) and a 45% risk reduction in worsening of renal function, end-stage renal disease, or renal death (hazard ratio 0.55, CI 0.48-0.64, p < 0.0001) with SGLT2i, irrespective of baseline estimated glomerular filtration rate. Thus, there is emerging evidence that SGLT2i may be used to curb the mortality and improve the quality of life in patients with DKD. However, clinicians need to effectively select candidates for SGLT2i therapy. In this consensus statement, we have qualitatively synthesized evidence demonstrating the renal effects of SGLT2i and proposed recommendations for optimal use of SGLT2i to effectively manage and delay progression of DKD.

Type 2 diabetes and influence of diabetes-specific distress on depression.

AIMS: Common psycho-social emotional reactions of patients with diabetes may be termed as diabetes-specific distress which is conceptually distinctive from depression. In patients with type 2 diabetes, different screening methods for depression may get influenced by simultaneous presence of diabetes distress. This study was planned to assess magnitude and relationship of depression and diabetes specific distress in patients with type 2 diabetes. METHODS: Two hundred and fifty (250) adult patients with type 2 diabetes (T2DM) were assessed for depression based on Beck Depression Inventory (BDI) and Diagnostic and Statistical Manual, Fourth edition (DSM IV) criteria. Diabetes specific distress was assessed as per Diabetes Distress Scale (DDS) score. RESULTS: Among study population of 250 adult T2DM patients, based on BDI score, 97 (38.8%) patients were found to suffer from depression and based on DSM IV criteria, prevalence of depression was 29.2%. A total of 62 (24.8%) patients were found to suffer from diabetes specific distress based on DDS score. Patients with severe diabetes specific distress had associated matching of symptoms with mild depression based on BDI score which was also statistically significant (p < 0.0001). However, these same individuals were non-depressed as per DSM-IV criteria. CONCLUSION: Recognizing depression with self-administered questionnaires may be influenced by concomitant presence of symptoms due to diabetes specific distress. Therefore, proper diagnosis of depression may be established by structured clinical interview and psycho-social management of type 2 diabetes should possibly include both assessment of depression and diabetes specific distress.

Tuberculosis of the thyroid gland: two case reports.

Tuberculosis of the thyroid gland is a rare entity even in countries like India where tuberculosis is endemic. The patients may present with thyroid swelling, inflammation and very rarely thyroid dysfunction. Caseous necrosis and epithelioid cell granulomas on fine-needle aspiration cytology and histopathological examination are diagnostic. We present two cases of thyroid gland tuberculosis. One patient had subclinical thyrotoxicosis with presentation mimicking acute bacterial thyroiditis. The other patient had a solitary thyroid nodule with normal thyroid function. Involvement of other organs was absent in both cases. Proper diagnosis may avoid unnecessary surgical interventions.

A comparative study between total contact cast and pressure-relieving ankle foot orthosis in diabetic neuropathic foot ulcers.

Off-loading of the ulcer area is extremely important for the healing of plantar ulcers. Off-loading with total contact cast (TCC) may be superior to other off-loading strategies studied so far, but practical limitations can dissuade clinicians from using this modality. This study was conducted to evaluate the efficacy of TCC compared with that of a pressure-relieving ankle foot orthosis (PRAFO) in healing of diabetic neuropathic foot ulcers and their effect on gait parameters. Thirty adult diabetic patients attending the foot clinic with neuropathic plantar ulcers irrespective of sex, age, duration and type of diabetes were randomly assigned to 1 of 2 off-loading modalities (TCC and PRAFO). Main outcome measures were ulcer healing after 4 weeks of randomization and effect of each of the modalities on various gait parameters. The percentage reduction of the ulcer surface area at 4 weeks from baseline was 75.75 ± 9.25 with TCC and 34.72 ± 13.07 with PRAFO, which was significantly different (P < .001). The results of this study however, showed that most of the gait parameters were better with PRAFO than with TCC. This study comprehensively evaluated the well known advantages and disadvantages of a removable (PRAFO) and a nonremovable device (TCC) in the treatment of diabetic neuropathic foot ulcer. Further studies are needed involving larger subjects and using 3D gait analysis to collect more accurate data on gait parameters and wound healing with different off-loading devices.

Diabetic neuropathic cachexia in a young female.

A 42-year-old lady, a known diabetic presented with generalized body ache, severe burning sensation over her lower limbs, loss of weight (approximately 8 kg), loss of appetite, nausea, frequent vomiting, and altered bowel habits without history of fever or pain abdomen. Symmetrical wasting was noted in all limbs with bilateral proximal muscle weakness, particularly of lower limbs. Ankle jerks were absent with symmetrically decreased reflexes. nerve conduction velocity (NCV) revealed symmetrical distal axonal and demyelinating type of sensorimotor polyneuropathy. Hematological and gastrointestinal (GI) malignancy were excluded. Patient responded to antidepressants.

Thyroid associated orbitopathy with ocular myasthenia in primary hypothyroidism: Keep those eyes open.

Thyroid associated orbitopathy, although seen most commonly with thyrotoxicosis, is also known to occur in primary hypothyroidism. Myasthenia gravis is an autoimmune condition with an established association with autoimmune thyroid disease. We report the case of a patient who presented with recent onset unilateral ptosis that was fatigable with a history of proptosis since a year. On examination, she had a goiter, bilateral proptosis, restriction of upward gaze and adduction both eyes and normal pupils. Investigations revealed primary hypothyroidism with anti-thyroid peroxidase positive and anti-acetylcholine receptor antibody positive. Computerized tomography orbit showed thickening of medial and inferior rectus characteristic of thyroid orbitopathy. A diagnosis of primary hypothyroidism with thyroid orbitopathy with ocular myasthenia gravis was made. Patient is on Levothyroxine and anticholinesterase medications and is on follow-up. We present this case to highlight that the presence of ptosis in a patient with thyroid orbitopathy should alert the clinician to the possible coexistence of myasthenia gravis.

Hypophosphatemic rickets: A case of recurrent pathological fractures.

INTRODUCTION: Renal phosphate-wasting disorders are the most common form of hereditary rickets and osteomalacia in western countries, but are rarely reported in India. Therefore, we report here a case of hypophosphatemic rickets. AIM AND OBJECTIVE: To report a case of hypophosphatemic rickets presenting with recurrent pathological fractures. MATERIAL AND METHODS: A 34-year-old premenopausal lady presented with recurrent pathological fractures, bone pain, and muscle weakness since 14 years of age. A thorough history was taken followed by clinical examination, and relevant biochemical and radiological investigations were done. RESULTS: Height was 125 cm, arm span 145 cm, body weight 30 kg, and body mass index (BMI) 19.2 kg/m(2). Dental caries, kyphoscoliosis, shortening of left lower limb, bilateral coxa vara deformity of knee, muscle weakness, and bone tenderness were present. Calcium was 9.4 mg/dL, phosphorus: 1.8 mg/dL, albumin: 4.0 gm/dL, alkaline phosphatase: 360 U/L, creatinine: 0.4 mg/dL, a normal ammonium chloride (NH4Cl) loading test,24-hour urine calcium excretion: 102 mg/day, 25-hydroxyvitamin D3 [25(OH)D3]: 21.6 ng/mL, intact parathyroid hormone (PTH): 43.74 pg/mL, fraction excretion of phosphate (PO4): 40%, tubular maximum reabsorption of phosphate per unit of glomerular filtrate (TmP/GFR): 0.65 mg/dL, and fibroblast growth factor (FGF)23: 321.4 RU/mL. Skeletal X-rays showed multiple old fractures and pseudofractures. Magnetic resonance imaging (MRI) of the whole body showed no evidence of tumor. Fludeoxyglucose ((18)F)-positron emission tomography (FDG-PET) computed tomography (CT) scan revealed metabolically active marrow with multiple areas of fracture and FDG-avid lesions in both lungs but no CT-based findings. CONCLUSION: Hypophosphatemic rickets or osteomalacia, possibly hereditary, is a rare cause of recurrent pathological fractures.