Immunotherapy in type 1 diabetes:Novel pathway to the future ahead

Since the discovery of insulin over 100 years ago,the focus of research in the management of type 1 diabetes(T1D)has centered around glycemic control and management of complications rather than the prevention of autoimmune destruc-tion of pancreaticβcells.Fortunately,in recent years,there has been significant advancement in immune-targeted pharmacotherapy to halt the natural progres-sion of T1D.The immune-targeted intervention aims to alter the underlying pa-thogenesis of T1D by targeting different aspects of the immune system.The im-munotherapy can either antagonize the immune mediators like T cells,B cells or cytokines(antibody-based therapy),or reinduce self-tolerance to pancreaticβcells(antigen-based therapy)or stem-cell treatment.Recently,the US Food and Drug Administration approved the first immunotherapy teplizumab to be used only in stage 2 of T1D.However,the window of opportunity to practically implement this approved molecule in the selected target population is limited.In this Edito-rial,we briefly discuss the various promising recent developments in the field of immunotherapy research in T1D.However,further studies of these newer thera-peutic agents are needed to explore their true potential for prevention or cure of T1D.

Type 2 diabetes in children and adolescents:Exploring the disease heterogeneity and research gaps to optimum management

Over the past 20 years,the incidence and prevalence of type 2 diabetes mellitus(T2DM)in children and adolescents have increased,particularly in racial and ethnic minorities.Despite the rise in T2DM in children and adolescents,the pathophysiology and progression of disease in this population are not clearly understood.Youth-onset T2DM has a more adverse clinical course than is seen in those who develop T2DM in adulthood or those with T1DM.Furthermore,the available therapeutic options are more limited for children and adolescents with T2DM compared to adult patients,mostly due to the challenges of implementing clinical trials.A better understanding of the mechanisms underlying the development and aggressive disease phenotype of T2DM in youth is important to finding effective prevention and management strategies.This review highlights the key evidence about T2DM in children and adolescents and its current burden and challenges both in clinical care and research activities.

Growth hormone and gastrointestinal malignancy:An intriguing link

Growth hormone(GH)excess is associated with several systemic complications,one of which is the increased risk of neoplastic processes particularly of the gastrointestinal(GI)tract.Among the GI neoplasms,the most reported association is with benign and malignant neoplasms of the colon.In the majority of published literature,an increased incidence of GI neoplasms,both colonic adenomas as well as colorectal carcinoma is reported.However,the studies on colon cancer-specific mortality rate are conflicting with recent studies reporting similar cancer-specific mortality rates in comparison to controls.Many studies have reported an association of colorectal neoplasms with GH levels.Pathogenic mechanisms put forward to explain this association of GH excess and GI neoplasms primarily involve the increased GH-insulin-like growth factor 1(IGF-1)signaling.Both GH and IGF-1 have proliferative,anti-apoptotic,and angiogenic effects on the systemic tissues leading to cellular proliferation.Other contributing factors to the increased risk of GI neoplasms include slow intestinal transit with a redundant large bowel,altered bile acids,deranged local immune response,shared genetic susceptibility factors and hyperinsulinemia.In view of the increased risk association,most guidelines for the care of acromegaly patients recommend an initial screening colonoscopy.Recommendations for further follow-up colonoscopy differ but broadly,the guidelines agree that it depends on the findings at first colonoscopy and state of remission of GH excess.Regarding the concern about the risk of colorectal cancers in patients receiving recombinant GH therapy,most cohort studies do not show an increased risk.

Role of bisphosphonates in the management of acute Charcot foot

Diabetes mellitus is the most common cause of Charcot neuropathy affecting foot and ankle. Acute Charcot foot(CF) presents with a red and swollen foot in co-ntrast to the painless deformed one of chronic CF. En-hanced osteoclastogenesis plays a central role in the pathogenesis of acute CF. Many studies have shown elevated levels of bone turnover markers in patients with acute CF confirming it. These findings have led cl-inicians to use anti-resorptive agents [bisphosphonates(BP), calcitonin, and denosumab] along with immobi-lization and offloading in acute CF patients. The ma-ximum evidence among all anti-resorptive agents is available for BPs, although its quality is low. Pamidronate has been shown to reduce the markers of activity of CF like raised skin temperature, pain, edema, and bone turnover markers in the majority of studies. Intravenous BPs are known to cause acute phase reactions leading to flu-like illness following their first infusion, which can be ameliorated by oral acetaminophen. Alendronate is the only oral BP used in these patients. It needs to be taken on an empty stomach with a full glass of water to avoid esophagitis. The side-effects and contraindications to BPs should be kept in mind while treating acute CF patients with them.

Critical review of bone health,fracture risk and management of bone fragility in diabetes mellitus

The risk of fracture is increased in both type 1 diabetes mellitus(T1DM)and type 2 diabetes mellitus(T2DM).However,in contrast to the former,patients with T2DM usually possess higher bone mineral density.Thus,there is a considerable difference in the pathophysiological basis of poor bone health between the two types of diabetes.Impaired bone strength due to poor bone microarchitecture and low bone turnover along with increased risk of fall are among the major factors behind elevated fracture risk.Moreover,some antidiabetic medications further enhance the fragility of the bone.On the other hand,antiosteoporosis medications can affect the glucose homeostasis in these patients.It is also difficult to predict the fracture risk in these patients because conventional tools such as bone mineral density and Fracture Risk Assessment Tool score assessment can underestimate the risk.Evidence-based recommendations for risk evaluation and management of poor bone health in diabetes are sparse in the literature.With the advancement in imaging technology,newer modalities are available to evaluate the bone quality and risk assessment in patients with diabetes.The purpose of this review is to explore the patho-physiology behind poor bone health in diabetic patients.Approach to the fracture risk evaluation in both T1DM and T2DM as well as the pragmatic use and efficacy of the available treatment options have been discussed in depth.

SGLT-2 inhibitors in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus: A systematic review

BACKGROUND Non-alcoholic fatty liver disease(NAFLD)is a common comorbidity with type 2 diabetes.The existing therapeutic options for NAFLD are not adequate.Hypocaloric diet and exercise is the cornerstone of therapy in NAFLD.Pioglitazone is the only drug recommended in diabetes patients with biopsy proven non-alcoholic steatohepatitis.The frequent coexistence of NAFLD and type 2 diabetes with their combined adverse health consequences and inadequate therapeutic options makes it necessary to search for newer alternatives.AIM To assess the effect of sodium glucose cotransporter-2(SGLT-2)inhibitors on liver enzymes in type 2 diabetes patients with NAFLD.METHODS We searched PubMed/MEDLINE,Cochrane library,Google scholar,and Clinicaltrials.gov for the relevant articles to be included in this systematic review.Human studies done in type 2 diabetes patients with NAFLD treated with SGLT-2 inhibitors for at least 12 wk were included.Data from eight studies(four randomised controlled trials and four observational studies)were extracted and a narrative synthesis was done.A total of 214 patients were treated with SGLT-2 inhibitors in these studies(94 in randomised controlled trials and 120 in observational studies).RESULTS The primary outcome measure was change in serum alanine aminotransferase level.Out of eight studies,seven studies showed a significant decrease in serum alanine aminotransferase level.Most of the studies revealed reduction in serum level of other liver enzymes like aspartate aminotransferase and gamma glutamyl transferase.Five studies that reported a change in hepatic fat exhibited a significant reduction in hepatic fat content in those treated with SGLT-2 inhibitors.Likewise,among the three studies that evaluated a change in indices of hepatic fibrosis,two studies revealed a significant improvement in liver fibrosis.Moreover,there was an improvement in obesity,insulin resistance,glycaemia,and lipid parameters in those subjects taking SGLT-2 inhibitors.The studies disclosed that about 17%(30/176)of the subjects taking SGLT-2 inhibitors developed adverse events and more than 40%(10/23)of them had genitourinary tract infections.CONCLUSION Based on low to moderate quality of evidence,SGLT-2 inhibitors improve the serum level of liver enzymes,decrease liver fat,and fibrosis with additional beneficial effects on various metabolic parameters in type 2 diabetes patients with NAFLD.

Heterogeneity of non-alcoholic fatty liver disease: Implications for clinical practice and research activity

Non-alcoholic fatty liver disease(NAFLD)is a heterogeneous condition with a wide spectrum of clinical presentations and natural history and disease severity.There is also substantial inter-individual variation and variable response to a different therapy.This heterogeneity of NAFLD is in turn influenced by various factors primarily demographic/dietary factors,metabolic status,gut microbiome,genetic predisposition together with epigenetic factors.The differential impact of these factors over a variable period of time influences the clinical phenotype and natural history.Failure to address heterogeneity partly explains the sub-optimal response to current and emerging therapies for fatty liver disease.Consequently,leading experts across the globe have recently suggested a change in nomenclature of NAFLD to metabolic-associated fatty liver disease(MAFLD)which can better reflect current knowledge of heterogeneity and does not exclude concomitant factors for fatty liver disease(e.g.alcohol,viral hepatitis,etc.).Precise identification of disease phenotypes is likely to facilitate clinical trial recruitment and expedite translational research for the development of novel and effective therapies for NAFLD/MAFLD.

Primary hyperparathyroidism presenting as acute pancreatitis: An institutional experience with review of the literature

BACKGROUND Acute pancreatitis(AP)presenting as an initial manifestation of primary hyperparathyroidism(PHPT)is uncommon,and its timely diagnosis is crucial in preventing recurrent attacks of pancreatitis.AIM To determine the clinical,biochemical,and radiological profile of PHPT patients presenting as AP.METHODS This is a retrospective observational study,51 consecutive patients admitted with the diagnosis of PHPT during January 2010 and October 2021 at a tertiary care hospital in Puducherry,India was included.The diagnosis of AP was established in the presence of at least two of the three following features:abdominal pain,levels of serum amylase or lipase greater than three times the normal,and characteristic features at abdominal imaging.RESULTS Out of the 51 consecutive patients with PHPT,twelve(23.52%)had pancreatitis[5(9.80%)AP,seven(13.72%)chronic pancreatitis(CP)].PHPT with AP(PHPT-AP)was more common among males with the presentation at a younger age(35.20±16.11 vs 49.23±14.80 years,P=0.05)and lower plasma intact parathyroid hormone(iPTH)levels[125(80.55-178.65)vs 519.80(149-1649.55,P=0.01)]compared to PHPT without pancreatitis(PHPT-NP).The mean serum calcium levels were similar in both PHPT-AP and PHPT-NP groups[(11.66±1.15 mg/dL)vs(12.46±1.71 mg/dL),P=0.32].PHPT-AP also presented with more gastrointestinal symptoms like abdominal pain,nausea,and vomiting with lesser skeletal and renal manifestations as compared to patients with PHPT-NP.CONCLUSION AP can be the only presenting feature of PHPT.Normal or higher serum calcium levels during AP should always draw attention towards endocrine causes like PHPT.