Sodium-glucose cotransporter 2 inhibitors: A comprehensive review from cells to bedside

Sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2is) are oral medications approved for type 2 diabetes mellitus. Interestingly, during recent years, they have been promisingly considered as new medications for cardiovascular and kidney diseases. However, the mechanisms underlying these new benefits are not fully understood. Thanks to the discovery of multiple modes of action, the simple picture about mechanisms of action of SGLT2is has become more and more complex. Besides their effects in diabetes, there is increasing evidence for their beneficial effects in heart failure and chronic kidney diseases. In addition, many studies have provided evidence for the fruitful effects of SGLT2is in atherosclerotic cardiovascular disease. In this study, we present mounting evidence for the complex action modes of SGLT2is and their current applications in clinical practice.     

Sodium–glucose cotransporter‐2 inhibitors induced euglycemic diabetic ketoacidosis: Two case reports and a review of the literature

If not detected early, euglycemic diabetic ketoacidosis can be a serious adverse effect of sodium–glucose cotransporter‐2 (SGLT2) inhibitors. Unfortunately, euglycemic diabetic ketoacidosis is underreported in recent trials and missed because of normal blood sugar levels and nonspecific symptoms on presentation. We present two patients with type 2 diabetes mellitus who developed dapagliflozin‐associated euglycemic diabetic ketoacidosis followed by hyperglycemic ketoacidosis. The second patient had euglycemic ketoacidosis twice despite instructions to stop using the medication dapagliflozin.     

Bilateral cerebral infarction in diabetic ketoacidosis and bilateral internal carotid artery occlusion: A case report and review of literature

BACKGROUNDDiabetic ketoacidosis (DKA) is a serious complication of type 1 diabetes mellitus (T1DM). Very rarely does DKA lead to cerebral edema, and it is even rarer for it to result in cerebral infarction. Bilateral internal carotid artery occlusion (BICAO) is also rare and can cause fatal stroke. Moreover, case reports about acute cerebral infarction throughout both internal carotid arteries with simultaneous BICAO are very scarce. In this study, we present a patient with BICAO, T1DM, hypertension, and hyperlipidemia, who had a catastrophic bilateral cerebral infarction after a DKA episode. We briefly introduce BICAO and the mechanisms by which DKA results in cerebral infarction. CASE SUMMARYA 41-year-old woman presented with ischemic stroke that took place 3 mo prior over the left corona radiata, bilateral frontal lobe, and parietal lobe with right hemiplegia and Broca’s aphasia. She had a history of hypertension for 5 years, hyperlipidemia for 4 years, hyperthyroidism for 3 years, and T1DM for 31 years. The first brain magnetic resonance imaging not only revealed the aforementioned ischemic lesions but also bilateral internal carotid artery occlusion. She was admitted to our ward for rehabilitation due to prior stroke sequalae. DKA took place on hospital day 2. On hospital day 6, she had a new massive infarction over the bilateral anterior cerebral artery and middle cerebral artery territory. After weeks of aggressive treatment, she remained in a coma and on mechanical ventilation due to respiratory failure. After discussion with her family, compassionate extubation was performed on hospital day 29 and she died.CONCLUSIONDKA can lead to cerebral infarction due to several mechanisms. In people with existing BICAO and several stroke risk factors such as hypertension, T1DM, hyperlipidemia, DKA has the potential to cause more serious ischemic strokes.     

Reversible global hypoperfusion in an adult patient with a mixed diabetic ketoacidosis/hyperglycemic hyperosmolar coma: A case report

Diabetic ketoacidosis is a severe complication of diabetes mellitus. We report a case of global hypoperfusion in an elderly patient on CT, with complete resolution shown on early MRI follow‐up. Metabolic causes have always to be included in the differential diagnosis of diffuse hypoperfusion in the appropriate clinical setting.     

PD-1抑制剂致胰岛β细胞功能急剧丧失后糖尿病2例报告

本文报道2例程序性死亡受体1(programmed death-1,PD-1)抑制剂导致的1型糖尿病。一例患者为53岁男性,因食管癌接受信迪利单抗联合艾越奈达铂治疗,使用6个周期后突然出现糖尿病酮症酸中毒；另一例为46岁女性,因恶性黑色素瘤接受卡瑞利珠单抗治疗14次后随访血糖过程中出现血糖明显升高,及时给予治疗。这2例患者空腹及葡萄糖负荷后血清Ｃ肽均处于极低水平,糖尿病相关抗体及自身抗体阴性,提示胰岛β细胞完全丧失。这两例患者均诊断为PD-1抑制剂相关1型糖尿病,需要长期餐时胰岛素及长效胰岛素强化治疗；但一例治疗过程中未随访血糖,突然以糖尿病酮症酸中毒起病；一例治疗中随访血糖,发现血糖高及时治疗,避免出现糖尿病急性并发症。因此对于使用PD-1抑制剂治疗的患者需要定期监测患者的血糖,及时发现血糖升高,给予相应治疗,避免出现严重并发症。     

Normoglycemic diabetic ketoacidosis in a type 2 diabetes patient on dapagliflozin: A case report

A 48‐year‐old male patient with Type 2 diabetes mellitus(T2D), on insulin replacement therapy, glipizide, and dapagliflozin presented with generalized weakness with weight loss of 40 pounds in 6 months ever since he was started on dapagliflozin. He was hemodynamically stable on arrival with a finger stick glucose of 121 gm%. Physical examination was unremarkable except for dry mucus membranes. His laboratory results on arrival are shown in Table 1. His serum osmolar gap was within the normal range. He was treated insulin drip per DKA protocol and gap was closed, the patient was clinically and biochemically back to baseline, and he was discharged home. Delayed diagnosis of normoglycemic diabetic ketoacidosis (DKA) in adults with diabetes treated with multiple antidiabetic drugs (eg, sodium‐glucose cotransporter‐2 [SGLT‐2] inhibitors) can potentially increase morbidity and mortality. Patient education in terms of symptoms and signs, physician awareness of early recognition of ketoacidosis in the setting of paradoxically normal or near‐normal blood glucose levels in these patients is the primary focus of this case study. This is paradoxical DKA because theoretically patient is not meeting one of the criteria for DKA which include triad of hyperglycemia, Ketoacidosis with widened anion gap, Ketonemia. This is a short case report of presumed SGLT‐2 inhibitor euglycemic diabetic ketoacidosis. The main teaching point is recognition and early diagnosis of this issue when multiple diabetic medications are present with the absence of hyperglycemia. This is, by current definition, not DKA because theoretically, the patient does not meet one of the criteria for DKA as the patient was apparently not hyperglycemic, albeit with, ketoacidosis and widened anion gap. (ketonemia)     

Nonocclusive mesenteric ischemia during treatment for ketoacidosis associated with acute‐onset type 1 diabetes mellitus: A case report

This case report describes a patient with nonocclusive mesenteric ischemia that developed due to diabetic ketoacidosis. We believe that early diagnosis and intervention may improve the prognosis of nonocclusive mesenteric ischemia that has low vascular risk, with the major risk factor being dehydration due to diabetic ketoacidosis.     

A case of diabetic ketoacidosis in a patient with COVID‐19 and newly diagnosed type 1 diabetes

To improve severe ketoacidosis with COVID‐19, insulin treatment, invasive mechanical ventilation therapy, and continuous hemodiafiltration with sodium bicarbonate infusion were effective.     

Development of dilated cardiomyopathy with a long latent period followed by viral fulminant myocarditis: A case report

BACKGROUNDThe clinical course of acute myocarditis ranges from the occurrence of a few symptoms to the development of fatal fulminant myocarditis. Specifically, fulminant myocarditis causes clinical deterioration very rapidly and aggressively. The long-term prognosis of myocarditis is varied, and it fully recovers without leaving any special complications. However, even after recovery, heart failure may occur and eventually progress to dilated cardiomyopathy (DCM), which causes serious left ventricular dysfunction. In the case of follow-up observation, no clear guidelines have been established.CASE SUMMARYWe report the case of a 21-year-old woman who presented with dyspnea. She became hemodynamically unstable and showed sustained fatal arrhythmias with decreased heart function. She was clinically diagnosed with fulminant myocarditis based on her echocardiogram and cardiac magnetic resonance results. After 2 d, she was readmitted to the emergency department under cardiopulmonary resuscitation and received mechanical ventilation and extracorporeal membrane oxygenation. An implantable cardioverter defibrillator was inserted for secondary prevention. She recovered and was discharged. Prior to being hospitalized for sudden cardiac function decline and arrhythmia, she had been well for 7 years without any complications. She was finally diagnosed with dilated cardiomyopathy.CONCLUSIONDCM may develop unexpectedly in patients who have been cured of acute fulminant myocarditis and have been stable with a long period of remission. Therefore, they should be carefully and regularly observed clinically throughout long-term follow-up.     

Nationwide survey to compare the prevalence of transient elevation of liver transaminase during treatment of diabetic ketosis or ketoacidosis in new-onset acute and fulminant type 1 diabetes mellitus

Background aims. A mild increase in liver enzyme levels is sometimes observed in patients with diabetic ketosis or ketoacidosis. The aim of the present study was to assess the cause and prevalence of the elevation of liver transaminase levels in fulminant and acute-onset type 1 diabetic patients experiencing diabetic ketosis or ketoacidosis.

Methods. We analyzed data on the liver transaminase levels of 108 patients over 18 years of age with newly diagnosed type 1 diabetes complicated by ketosis or ketoacidosis. The data were collated from a nationwide survey on fulminant type 1 diabetes and retrospective medical records.

Results. Thirty-two (60.4%) out of the 53 patients suffering from fulminant type 1 diabetes were detected with transient elevation of liver transaminase (TELT) levels during the first month after initiation of insulin therapy; in the case of acute-onset type 1 diabetes, such an observation was noted in 16 (29.1%) out of 55 patients. Fatty liver was diagnosed in 20% of the patients, and 65% of these patients exhibited TELT. The dosage of insulin injected in these patients was significantly high.

Conclusions. High blood glucose and fatty liver may influence the elevation of liver transaminase levels during the treatment of new-onset type 1 diabetes.     

Clinical study of autoantibodies in type 1 diabetes mellitus children with ketoacidosis or microalbuminuria

AimsThe study aimed to investigate the value of autoantibodies in predicting the risk of ketoacidosis or microalbuminuria in children with type 1 diabetes mellitus.MethodsClinical data and laboratory indicators of 80 patients with type 1 diabetes admitted to the Department of Endocrinology in Tianjin Children''s Hospital, from June 2017 to March 2019, were retrospectively analyzed. The patients were divided into two groups: diabetes without ketoacidosis group (n = 20) and diabetes with ketoacidosis group (n = 60). The differences in general data, laboratory test indexes, and autoantibodies between the two groups were analyzed. Finally, ROC curves and multivariate logistic regression analysis were used to explore the value of autoantibodies in patients with ketoacidosis or microalbuminuria.ResultsA total of 80 children with type 1 diabetes were assessed, including 35 boys and 45 girls, ranging in age from 10 months to 15 years. The concentration of GADA, IA2A, and ZnT8A was not statistically different between the two groups, but the positive rate of ZnT8A was statistically significant (p = 0.038) and had a diagnostic value for the occurrence of ketoacidosis (p = 0.025). ZnT8A‐positive patients had a higher titer of IA2A and a more frequent prevalence of GADA and IA2A than ZnT8A‐negative patients (p < 0.01). In multivariate logistic regression analyses, the presence of positive ZnT8A was associated with a higher risk of microalbuminuria independent of age, sex, and BMI (OR = 4.184 [95% CI 1.034~16.934], p = 0.045).ConclusionsThe positive ZnT8A had diagnostic value for ketoacidosis in children with type 1 diabetes and had the highest specificity among the three kinds of autoantibodies. Moreover, ZnT8A positivity was related to a higher titer of IA2A and more frequent occurrence of multiple diabetes‐related autoantibodies. Besides, the presence of positive ZnT8A was an independent risk factor of microalbuminuria in children with type 1 diabetes. Therefore, we can infer that positive ZnT8A may be related to ketoacidosis and microalbuminuria, accelerating the progression of T1DM.     

Managing spondylitis tuberculosis in a patient with underlying diabetes and hypothyroidism: A case report

BACKGROUNDTuberculosis (TB) remains one of the highest Asia’s health problems. Spondylitis TB in diabetes mellitus (DM) and hypothyroidism patients is a rare case of extrapulmonary tuberculosis. However, there is a lack of therapeutic guidelines to treat spondylitis TB, particularly with type 2 DM (T2DM) and hypothyroidism as comorbidities. Here we present a case of spondylitis TB with T2DM and hypothyroidism in a relatively young patient and its therapeutic procedure.CASE SUMMARYWe report the case of a 35-year-old male patient from Surabaya, Indonesia. Based on anamnesis, physical examination, and magnetic resonance imaging, the patient has been categorized in stage II of spondylitis TB with grade 1 paraplegia. Surprisingly, the patient also had a high HbA1c level, high thyroid stimulating hormone, and low free T₄ (FT₄), which indicated T2DM and hypothyroidism. A granulomatous process was observed in the histopathological section. The antituberculosis drugs isoniazid and rifampicin were given. In addition, insulin, empagliflozin, and linagliptin were given to control hyperglycemia conditions, and also levothyroxine to control hypothyroidism.CONCLUSIONThe outcome was satisfactory. The patient was able to do daily activities without pain and maintained normal glycemic and thyroid levels. For such cases, we recommend the treatment of spondylitis TB by spinal surgery, together with T2DM and hypothyroidism therapies, to improve the patients’ condition. Prompt early and non-invasive diagnoses and therapy are necessary.     

胰高糖素样肽-1激动剂联合钠-葡萄糖协同转运蛋白2抑制剂对2型糖尿病的影响

近年来,全球糖尿病患病率逐年增加,其中2型糖尿病(type 2 diabetes mellitus,T2DM)占糖尿病总患病人数的90%~95%。胰高糖素样肽-1(glucagon-like peptide 1,GLP-1)激动剂联合钠-葡萄糖协同转运蛋白2抑制剂(sodium-glucose co-transporter 2 inhibitor,SGLT2)是治疗T2DM的新型降糖药物。本文讨论在给予规范的生活方式(饮食和运动)干预下,GLP-1激动剂联合SGLT2抑制剂对T2DM的安全性和有效性。     

钠-葡萄糖共转运蛋白2抑制剂对伴有严重肾功能不全的2型糖尿病患者心血管保护作用的Meta分析

目的 评价钠-葡萄糖共转运蛋白2(sodium-glucose cotransporter 2,SGLT2)抑制剂对伴严重肾功能不全的2型糖尿病患者(diabetes mellitus type 2,T2DM)心血管保护作用及其不良反应.方法 检索Medline、Embase和Cochrane Library数据库,收...     

Familial left cervical neurofibromatosis 1 with scoliosis: A case report

BACKGROUNDNeurofibromatosis type 1 (NF1) is an inherited autosomal dominant disorder affecting many parts of the body with café au lait spots, skeletal deformity, and scoliosis. A familial case of NF1 with scoliosis and a painless mass had not yet been reported.CASE SUMMARYWe describe the case of a 15-year-old male patient with a painless lump on the left side of his neck for 10 years and scoliosis. His right shoulder was about 5 cm lower than the left, the left side of his face was deformed, and the left submandibular skin was relaxed. The folding and drooping were obvious and movement was poor. Computed tomography revealed the involvement of the neck, upper chest wall, and surrounding left shoulder, accompanied by bone changes and scoliosis. Histological evaluation showed subepidermal pale blue mucoid degeneration, fibrous fusiform cells in the dermis in a fascicular, woven arrangement. His mother had the same medical history. The diagnosis was neurofibromatosis of the left neck. Various parts of the tumor tissue were serially resected during several visits. Eight months after surgery, there was a slight tendency to regrow.CONCLUSIONThis case of slow-progressing NF1 highlights the importance of early diagnosis and treatment to reduce its impact on the patient’s growth and development.     

Congenital nephrogenic diabetes insipidus arginine vasopressin receptor 2 gene mutation at new site: A case report

BACKGROUNDCongenital nephrogenic diabetes insipidus (CNDI) is a rare hereditary disorder. It is associated with mutations in the arginine vasopressin receptor 2 (AVPR2) gene and aquaporin 2 (AQP2) gene, and approximately 270 different mutation sites have been reported for AVPR2. Therefore, new mutations and new manifestations are crucial to complement the clinical deficiencies in the diagnosis of this disease. We report a case of a novel AVPR2 gene mutation locus and a new clinical mani-festation.CASE SUMMARYWe describe the case of a 48-d-old boy who presented with recurrent fever and diarrhea 5 d after birth. Laboratory tests showed electrolyte disturbances and low urine specific gravity, and imaging tests showed no abnormalities. Genetic testing revealed a novel X-linked recessive missense mutation, c.283 (exon 2) C>T (p.P95S). This mutation results in the substitution of a proline residue with a serine residue in the AVPR2 protein sequence. The diagnosis of CNDI was confirmed based on the AVPR2 gene mutation. The treatment strategy for this patient was divided into two stages, including physical cooling supplemented with appropriate amounts of water in the early stage and oral hydrochlorothia-zide (1-2 mg/kg) after a clear diagnosis. After follow-up of one and a half years, the patient gradually improved.CONCLUSIONAVPR2 gene mutations in new loci and new clinical symptoms help clinicians understand this disease and shorten the diagnosis cycle.     

HbA1c对糖调节受损和2型糖尿病的诊断价值

摘要：目的：评估糖化血红蛋白（HbA1c）不同cut off值诊断2型糖尿病（T2DM）的效能,初步探讨美国糖尿病协会（ADA）推荐的HbA1c诊断T2DM及T2DM前期标准对中国人的适用性。 方法：招募接受口服葡萄糖耐量（OGTT）试验且试验前未诊治为T2DM的志愿者338例,用高效液相色谱法检测HbA1c;以WHO标准诊断糖调节受损（IGR）、糖耐量正常和T2DM;用受试者工作特征（ROC）曲线分析不同 cut off值HbA1c诊断IGR和T2DM的效能。 结果：HbA1c在诊断T2DM时,ROC曲线下面积（AUC^ROC）为0.954,最佳cut off值为6.0%,敏感性为92.5%,特异性为86.0%;当HbA1c为6.5%时,敏感性为64.8%,特异性为96.7%;当HbA1c为5.6%时,诊断T2DM阴性预测值为100.0%;HbA1c诊断IGR的AUC^ROC为0.653。 结论: HbA1c用于IGR的诊断效能不高;HbA1c诊断T2DM最佳cut off值为6.0%,此界值诊断敏感性较FPG高,但特异性较差;ADA推荐用于T2DM诊断的cut off值6.5%主要考虑到诊断的特异性,该诊断标准适用于中国人群。