The Roles of Non-Pharmacologic and Emerging Pharmacologic Management of Non-alcoholic Fatty Liver Disease and Sarcopenia: A Narrative Review.

Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent causes of chronic liver disease worldwide which is often seen in patients with metabolic abnormalities such as those with obesity and insulin resistance. On the other hand, sarcopenia is a generalized and progressive skeletal muscle disorder characterized by low muscle strength, low muscle quality, low physical performance, or a combination of the three. Both disease entities share several underlying risk factors and pathophysiologic mechanisms. These include: (1) cardiometabolic overlaps such as insulin resistance, chronic systemic inflammation, decreased vitamin D levels, sex hormone modifications; (2) muscle-related factors such as those mitigated by myostatin signaling, and myokines (i.e., irisin); and (3) liver-dysfunction related factors such as those associated with growth hormone/insulin-like growth factor 1 Axis, hepatokines (i.e., selenoprotein P and leukocyte cell-derived chemotaxin-2), fibroblast growth factors 21 and 19 (FGF21 and FGF19), and hyperammonemia. This narrative review will examine the pathophysiologic overlaps that can explain the links between NAFLD and sarcopenia. Furthermore, this review will explore the emerging roles of nonpharmacologic (e.g., weight reduction, diet, alcohol, and smoking cessation, and physical activity) and pharmacologic management (e.g., roles of ß-hydroxy-ß-methylbutyrate, branched-chain amino acid supplements, and testosterone therapy) to improve care, intervention sustainability, and acceptability for patients with sarcopenia-associated NAFLD.

Interrelationship of Sarcopenia and Cardiovascular Diseases: A Review of Potential Mechanisms and Management.

Sarcopenia refers to an age-related reduction of lean body mass. It showed a reciprocal relationship with cardiovascular diseases. Thus, it is imperative to explore pathophysiological mechanisms explaining the relationship between sarcopenia and cardiovascular diseases, along with the clinical assessment, and associated management. In this review, we discuss how processes such as inflammation, oxidative stress, endothelial dysfunction, neural and hormonal modifications, as well as other metabolic disturbances influence sarcopenia as well as its association with cardiovascular diseases. Moreover, this review provides an overview of both non-pharmacological and pharmacological management for patients with sarcopenia and cardiovascular diseases, with a focus on the potential role of cardiovascular drugs to mitigate sarcopenia.

Protective Factors and the Pathogenesis of Complications in Diabetes.

Chronic complications of diabetes are due to myriad disorders of numerous metabolic pathways that are responsible for most of the morbidity and mortality associated with the disease. Traditionally, diabetes complications are divided into those of microvascular and macrovascular origin. We suggest revising this antiquated classification into diabetes complications of vascular, parenchymal, and hybrid (both vascular and parenchymal) tissue origin, since the profile of diabetes complications ranges from those involving only vascular tissues to those involving mostly parenchymal organs. A major paradigm shift has occurred in recent years regarding the pathogenesis of diabetes complications, in which the focus has shifted from studies on risks to those on the interplay between risk and protective factors. While risk factors are clearly important for the development of chronic complications in diabetes, recent studies have established that protective factors are equally significant in modulating the development and severity of diabetes complications. These protective responses may help explain the differential severity of complications, and even the lack of pathologies, in some tissues. Nevertheless, despite the growing number of studies on this field, comprehensive reviews on protective factors and their mechanisms of action are not available. This review thus focused on the clinical, biochemical, and molecular mechanisms that support the idea of endogenous protective factors, and their roles in the initiation and progression of chronic complications in diabetes. In addition, this review also aimed to identify the main needs of this field for future studies.

Metabolic Profile of People Living with HIV in a Treatment Hub in Manila, Philippines: A Pre- and Post-Antiretroviral Analysis.

Objectives: People living with HIV (PLHIV) are susceptible to develop dyslipidemia and hyperglycemia. This study aims to determine the prevalence of these metabolic derangements among Filipino PLHIV. Methodology: We reviewed 635 medical records in a treatment hub in Manila, Philippines from January 2004 to July 2016. Logistic regression analysis was done to determine factors associated with dyslipidemia and hyperglycemia pre- and post-ART. Results: Among 635 PLHIV, 97.3% were males with mean age of 30 years and median CD4 count of 207 cells/mm3. Pre-ART, prevalence of dyslipidemia was 65.4% and hyperglycemia was 10.4%. Risk factors for dyslipidemia include hyperglycemia (AOR 3.8, p 0.001) and >320 days delay in ART initiation from HIV confirmation (AOR 1.5, p 0.032), while dyslipidemia was associated with hyperglycemia (AOR 3.1, p 0.001). Post-ART, prevalence of dyslipidemia was 48.6% and hyperglycemia was 15.6%. Risk factors for post-ART dyslipidemia include being WHO stage 4 (AOR 2.1, p 0.021), hyperglycemia (AOR 16.1, p<0.001), >36 months ART duration (AOR 8.7, p<0.001) and efavirenz-based ART (AOR 2.8, p<0.001). Low CD4 count post-ART had a negative correlation with dyslipidemia (AOR 0.5, p 0.005). Post-ART hyperglycemia was associated with age >30 years (AOR 2.1, p 0.004), being overweight (AOR 1.8, p 0.023), dyslipidemia (AOR 17.8, p<0.001) and zidovudine-based ART (AOR 1.4, p 0.051). Conclusion: Dyslipidemia and hyperglycemia prevalence was high in Filipino PLHIV. Traditional, HIV and treatment related factors contributed to its development. Intensive monitoring and initiation of appropriate treatment is recommended.

Endothelial Cells Induced Progenitors Into Brown Fat to Reduce Atherosclerosis.

BACKGROUND: Insulin resistance (IR) can increase atherosclerotic and cardiovascular risk by inducing endothelial dysfunction, decreasing nitric oxide (NO) production, and accelerating arterial inflammation. The aim is to determine the mechanism by which insulin action and NO production in endothelial cells can improve systemic bioenergetics and decrease atherosclerosis via differentiation of perivascular progenitor cells (PPCs) into brown adipocytes (BAT). METHODS: Studies used various endothelial transgenic and deletion mutant ApoE-/- mice of insulin receptors, eNOS (endothelial NO synthase) and ETBR (endothelin receptor type B) receptors for assessments of atherosclerosis. Cells were isolated from perivascular fat and micro-vessels for studies on differentiation and signaling mechanisms in responses to NO, insulin, and lipokines from BAT. RESULTS: Enhancing insulin's actions on endothelial cells and NO production in ECIRS1 transgenic mice reduced body weight and increased systemic energy expenditure and BAT mass and activity by inducing differentiation of PPCs into beige/BAT even with high-fat diet. However, positive changes in bioenergetics, BAT differentiation from PPCs and weight loss were inhibited by N(gamma)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of eNOS, in ECIRS1 mice and eNOSKO mice. The mechanism mediating NO's action on PPC differentiation into BAT was identified as the activation of solubilized guanylate cyclase/PKGIα (cGMP protein-dependent kinase Iα)/GSK3ß (glycogen synthase kinase 3ß) pathways. Plasma lipidomics from ECIRS1 mice with NO-induced increased BAT mass revealed elevated 12,13-diHOME production. Infusion of 12,13-diHOME improved endothelial dysfunction and decreased atherosclerosis, whereas its reduction had opposite effects in ApoE-/-mice. CONCLUSIONS: Activation of eNOS and endothelial cells by insulin enhanced the differentiation of PPC to BAT and its lipokines and improved systemic bioenergetics and atherosclerosis, suggesting that endothelial dysfunction is a major contributor of energy disequilibrium in obesity.

Self-reported cultural competency measures among patients with diabetes: A nationwide cross-sectional study in the United States.

Background: Culturally tailored interventions may reduce disparities in diabetes care. We conducted a nationally representative assessment of self-reported cultural competency measures of care among patients with diabetes in the United States. Methods: The 2017 National Health Interview Survey was queried for adults with self-reported diabetes. Sample weight-adjusted multivariable logistic regressions defined adjusted odds ratios and 95% confidence intervals of a positive response to each of the cultural competency measures while controlling for relevant sociodemographic variables. Findings: 2,448 adults were included in the analyses. Black, Latinx, and Asian respondents had greater odds of and individuals with the highest income level had lower odds of placing greater importance in sharing cultures with their provider. Black and Latinx individuals had lower odds of reporting encountering providers who shared or understood their cultures. Asians had lower odds of and respondents aged 40-64 and 65 years and older had greater odds of reporting frequently being treated with respect by their providers. Non-English speakers had lower odds of and individuals from higher income brackets had greater odds of reporting frequently receiving easy-to-understand information about their care. Blacks and respondents not part of the workforce had greater odds of reporting frequently being asked about their opinions or beliefs in care. Interpretation: Disparities in self-reported provider cultural competency measures exist among cultural minorities in the United States. Our findings may inform efforts to reduce disparities and improve care among minorities with diabetes. Funding: No funding was used in the preparation of this work.

Insulin's actions on vascular tissues: Physiological effects and pathophysiological contributions to vascular complications of diabetes.

BACKGROUND: Insulin has been demonstrated to exert direct and indirect effects on vascular tissues. Its actions in vascular cells are mediated by two major pathways: the insulin receptor substrate 1/2-phosphoinositide-3 kinase/Akt (IRS1/2/PI3K/Akt) pathway and the Src/mitogen-activated protein kinase (MAPK) pathway, both of which contribute to the expression and distribution of metabolites, hormones, and cytokines. SCOPE OF REVIEW: In this review, we summarize the current understanding of insulin's physiological and pathophysiological actions and associated signaling pathways in vascular cells, mainly in endothelial cells (EC) and vascular smooth muscle cells (VSMC), and how these processes lead to selective insulin resistance. We also describe insulin's potential new signaling and biological effects derived from animal studies and cultured capillary and arterial EC, VSMC, and pericytes. We will not provide a detailed discussion of insulin's effects on the myocardium, insulin's structure, or its signaling pathways' various steps, since other articles in this issue discuss these areas in depth. MAJOR CONCLUSIONS: Insulin mediates many important functions on vascular cells via its receptors and signaling cascades. Its direct actions on EC and VSMC are important for transporting and communicating nutrients, cytokines, hormones, and other signaling molecules. These vascular actions are also important for regulating systemic fuel metabolism and energetics. Inhibiting or enhancing these pathways leads to selective insulin resistance, exacerbating the development of endothelial dysfunction, atherosclerosis, restenosis, poor wound healing, and even myocardial dysfunction. Targeted therapies to improve selective insulin resistance in EC and VSMC are thus needed to specifically mitigate these pathological processes.

Association of Cognitive Function and Retinal Neural and Vascular Structure in Type 1 Diabetes.

CONTEXT: Cognitive dysfunction is a growing and understudied public health issue in the aging type 1 diabetic population and is difficult and time-consuming to diagnose. Studies in long duration type 1 diabetes have reported the presence of proliferative diabetic retinopathy was associated with cognitive dysfunction. OBJECTIVE: This study assessed whether structural and vascular abnormalities of the retina, representing an extension of the central nervous system, are associated with cognitive impairment and other complications of type 1 diabetes. METHODS: An observational cross-sectional study of individuals with 50 or more years of type 1 diabetes (Joslin Medalist Study) was conducted at a university hospital in the United States. The study included 129 participants with complete cognitive testing. Validated cognitive testing measures included psychomotor speed, and immediate, and delayed memory. Optical coherence tomography (OCT) and OCT angiography (OCTA) were performed to obtain neural retinal layer thicknesses and vascular density for superficial (SCP) and deep retinal capillary plexus (DCP). Multivariable modeling was adjusted for potential confounders associated with outcomes in unadjusted analyses. RESULTS: Decreased vessel density of the SCP and DCP was associated with worse delayed memory (DCP: P = .002) and dominant hand psychomotor speed (SCP: P = .01). Thinning of the retinal outer nuclear layer was associated with worse psychomotor speed both in nondominant and dominant hands (P = .01 and P = .05, respectively). Outer plexiform layer thickness was associated with delayed memory (P = .04). CONCLUSION: These findings suggest that noninvasive retinal imaging using OCT and OCTA may assist in estimating the risks for cognitive dysfunction in people with type 1 diabetes.

Association of sunlight exposure with 25-hydroxyvitamin D levels among working urban adult Filipinos.

OBJECTIVES: To determine the association of different levels of sunlight exposure, measured using the Filipino sunlight exposure questionnaire (SEQ) with 25-hydroxyvitamin D (25-OHD) levels among working urban adult Filipinos. METHODS: Seventy-five adult participants, living and working in Metro Manila, for at least 1 year, were grouped according to their perceived sunlight exposure pattern: low sunlight exposure (mostly indoor work); moderate sunlight exposure (both indoor and outdoor work); and high sunlight exposure (mostly outdoor work). After completion of the self-administered Filipino SEQ, they underwent serum 25-OHD level determination. Strength of correlation between the SEQ scores and 25-OHD levels was computed. RESULTS: Serum 25-OHD levels generally increased with increasing sunlight exposure levels. The overall Pearson's correlation between the SEQ scores and 25-OHD levels of the participants was 0.396 (P = 0.001). The correlation for the individual domains was 0.342 for intensity of sunlight exposure (P = 0.003), 0.321 for factors affecting sunlight exposure (P = 0.005), and 0.256 for sun protection practices (P = 0.027). CONCLUSIONS: The sunlight exposure of working urban adult Filipinos, as measured by the Filipino SEQ, has an overall significant, direct and moderate association with serum 25-OHD levels. This Filipino SEQ can serve as a valuable clinical tool for sunlight exposure assessment to identify individuals at risk for vitamin D deficiency.

Residual ß cell function and monogenic variants in long-duration type 1 diabetes patients.

BACKGROUNDIn the Joslin Medalist Study (Medalists), we determined whether significant associations exist between ß cell function and pathology and clinical characteristics.METHODSIndividuals with type 1 diabetes (T1D) for 50 or more years underwent evaluation including HLA analysis, basal and longitudinal autoantibody (AAb) status, and ß cell function by a mixed-meal tolerance test (MMTT) and a hyperglycemia/arginine clamp procedure. Postmortem analysis of pancreases from 68 Medalists was performed. Monogenic diabetes genes were screened for the entire cohort.RESULTSOf the 1019 Medalists, 32.4% retained detectable C-peptide levels (>0.05 ng/mL, median: 0.21 ng/mL). In those who underwent a MMTT (n = 516), 5.8% responded with a doubling of baseline C-peptide levels. Longitudinally (n = 181, median: 4 years), C-peptide levels increased in 12.2% (n = 22) and decreased in 37% (n = 67) of the Medalists. Among those with repeated MMTTs, 5.4% (3 of 56) and 16.1% (9 of 56) had waxing and waning responses, respectively. Thirty Medalists with baseline C-peptide levels of 0.1 ng/mL or higher underwent the clamp procedure, with HLA-/AAb- and HLA+/AAb- Medalists being most responsive. Postmortem examination of pancreases from 68 Medalists showed that all had scattered insulin-positive cells; 59 additionally had few insulin-positive cells within a few islets; and 14 additionally had lobes with multiple islets with numerous insulin-positive cells. Genetic analysis revealed that 280 Medalists (27.5%) had monogenic diabetes variants; in 80 (7.9%) of these Medalists, the variants were classified as "likely pathogenic" (rare exome variant ensemble learner [REVEL] >0.75).CONCLUSIONAll Medalists retained insulin-positive ß cells, with many responding to metabolic stimuli even after 50 years of T1D. The Medalists were heterogeneous with respect to ß cell function, and many with HLA+ diabetes risk alleles also had monogenic diabetes variants, indicating the importance of genetic testing for clinically diagnosed T1D.FUNDINGFunding for this work was provided by the Dianne Nunnally Hoppes Fund; the Beatson Pledge Fund; the NIH, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); and the American Diabetes Association (ADA).

Development and validation of a sunlight exposure questionnaire for urban adult Filipinos.

OBJECTIVES: To develop and validate a self-reported sunlight exposure questionnaire (SEQ) for urban adult Filipinos. METHODS: The study included adults (19-76 years old) in Metro Manila, Philippines, well-versed in the Filipino (Tagalog) language and had resided in Metro Manila for at least 1 year. Exclusion criteria included pregnancy, active skin disorders, and immunocompromised states. An expert panel created a questionnaire in Likert-scale format based on a conceptual framework and 4 existing instruments. The study proceeded in 4 phases: questionnaire item development, translation and back-translation, pretesting, and construct validity and reliability testing using factor analysis, the Cronbach alpha coefficient, and the paired t-test. RESULTS: A 25-item, self-administered, Filipino (Tagalog) SEQ answerable using a 4-point Likert scale was created. The questionnaire was administered to 260 adult participants twice at a 2-week interval, with all participants completing both the first and second rounds of testing. All questionnaire items possessed adequate content validity indices of at least 0.86. After factor analysis, 3 questionnaire domains were identified: intensity of sunlight exposure, factors affecting sunlight exposure, and sun protection practices. Internal consistency was satisfactory for both the overall questionnaire (Cronbach alpha, 0.80) and for each of the domains (Cronbach alpha, 0.74, 0.71, and 0.72, respectively). No statistically significant differences were observed in the responses between the first and second rounds of testing, indicating good test-retest reliability. CONCLUSIONS: We developed a culturally-appropriate SEQ with sufficient content validity, construct validity, and reliability to assess sunlight exposure among urban adult Filipinos in Metro Manila, Philippines.

Attitudes, Behaviors and Beliefs of Urban Adult Filipinos on Sunlight Exposure: A Qualitative Study.

OBJECTIVE: To explore the attitudes, behaviors, and beliefs of urban adult Filipinos on sunlight exposure as an initial step in the development and validation of a culturally-appropriate questionnaire. METHODOLOGY: Focus groups were conducted among urban Filipinos 19 years old and above (n=38). The transcribed results underwent qualitative content and thematic analyses and were used to develop a conceptual framework. RESULTS: Qualitative analysis revealed four main themes of sunlight exposure: internal influences, external influences, perceived benefits, and perceived risks. Both internal and external influences lead to perceived risks and benefits. Consequently, the perceived benefits (or lack) of sunlight exposure influence an individual's attitude towards vitamin D supplementation; whereas the perceived risks of sunlight exposure influence an individual's attitude towards the need for sun protection. CONCLUSION: The attitudes, behaviors and beliefs of urban adult Filipinos on sunlight exposure are influenced by both internal and external factors, that in turn lead to perceived risks and benefits. An increased awareness of these factors is necessary to establish future recommendations on proper sunlight exposure in this population. The study results will be used to develop and validate a culturally-appropriate sunlight exposure questionnaire.

Factors Associated with Postoperative Diabetes Insipidus after Pituitary Surgery.

BACKGROUND: Determining risk factors for diabetes insipidus (DI) after pituitary surgery is important in improving patient care. Our objective is to determine the factors associated with DI after pituitary surgery. METHODS: We reviewed records of patients who underwent pituitary surgery from 2011 to 2015 at Philippine General Hospital. Patients with preoperative DI were excluded. Multiple logistic regression analysis was performed and a predictive model was generated. The discrimination abilities of the predictive model and individual variables were assessed using the receiving operator characteristic curve. RESULTS: A total of 230 patients were included. The rate of postoperative DI was 27.8%. Percent change in serum Na (odds ratio [OR], 1.39; 95% confidence interval [CI], 1.15 to 1.69); preoperative serum Na (OR, 1.19; 95% CI, 1.02 to 1.40); and performance of craniotomy (OR, 5.48; 95% CI, 1.60 to 18.80) remained significantly associated with an increased incidence of postoperative DI, while percent change in urine specific gravity (USG) (OR, 0.53; 95% CI, 0.33 to 0.87) and meningioma on histopathology (OR, 0.05; 95% CI, 0.04 to 0.70) were significantly associated with a decreased incidence. The predictive model generated has good diagnostic accuracy in predicting postoperative DI with an area under curve of 0.83. CONCLUSION: Greater percent change in serum Na, preoperative serum Na, and performance of craniotomy significantly increased the likelihood of postoperative DI while percent change in USG and meningioma on histopathology were significantly associated with a decreased incidence. The predictive model can be used to generate a scoring system in estimating the risk of postoperative DI.

Poorly Differentiated Thyroid Carcinoma: 10-Year Experience in a Southeast Asian Population.

BACKGROUND: No previous studies have been published on poorly differentiated thyroid carcinoma (PDTC) in Southeast Asia. METHODS: We included all adult PDTC patients diagnosed using the Turin criteria at the Philippine General Hospital from 2006 to 2015. The data collected included demographics, clinical presentation, histopathology, treatment, and outcomes. Tests of association were employed to compare these data with foreign studies on PDTC, as well as with local studies on well differentiated thyroid carcinoma (WDTC) and anaplastic thyroid carcinoma (ATC). RESULTS: Eighteen PDTC cases were identified. The median age was 62 years old, with the majority being females. All patients had goiter on presentation, and most were stage IV at the time of diagnosis. In terms of PDTC subtype, insular and trabecular patterns were equally common. Extrathyroidal extension was documented in eight patients, while five patients each had nodal and distant metastasis. All but one patient underwent surgery; however, less than half received adjuvant radioiodine therapy. The 5-year survival rate was 83%. Three patients (16.7%) died at a median of 12 months after diagnosis. Nine (50%) are still alive with persistent and/or recurrent disease at a median of 39 months after diagnosis. CONCLUSION: The behavior of PDTC in this Southeast Asian population was found to be similar to patterns observed in other regions, and exhibited intermediate features between WDTC and ATC. Appropriate surgery provided excellent 5-year survival rates, but the role of adjuvant therapy remains unclear. Larger studies are needed to identify prognostic factors in this population.

Acute mania after levothyroxine replacement for hypothyroid-induced heart block.

Psychiatric disturbances can manifest after levothyroxine (LT4) treatment for severe hypothyroidism. We present the case of a young Filipino man with Hashimoto's thyroiditis and high-grade heart block, who was given a full replacement LT4 dose on admission. Twenty-four hours after this dose, he developed manic symptoms, which were addressed with sedatives and neuroleptics with gradual restoration of euthymia the following day. A comprehensive workup did not reveal any findings suggestive of another aetiology for either mania or heart block. We ultimately ascribed the mania as secondary to LT4, and the heart block to hypothyroidism. Although mania is more likely to be precipitated by high starting LT4 doses, reports have shown that symptoms can still arise even at lower doses and with more gradual titration, especially in long-standing hypothyroidism.

Limited cutaneous systemic sclerosis arising in a patient with Graves' disease.

Although Graves' disease and systemic sclerosis are both autoimmune disorders, their relationship is rarely reported. We present the case of a Filipino woman with goitre and thyrotoxic signs and symptoms. Diagnosed with Graves' disease at the outpatient clinic, she took antithyroid medications and underwent radioactive iodine ablation with resultant hypothyroidism after 6 months, during which she began to experience skin tightness over the face, neck and fingers. Workup revealed limited cutaneous systemic sclerosis, and the patient improved with methotrexate. This case highlights the increased prevalence of coincident autoimmune disorders in Graves' disease.

Efficacy of Heparinoid Supplementation on Mortality and Disease Progression in Adults with Diabetic Kidney Disease.

OBJECTIVE: To evaluate the safety and efficacy of heparinoid supplementation on all-cause mortality and disease progression in diabetic kidney disease (DKD). METHODOLOGY: Trials evaluating heparinoid supplementation in DKD were included. Two authors performed a literature search with eligible studies undergoing validity screen, data extraction, and statistical analysis. Results were calculated using the Mantel-Haenszel odds ratio for dichotomous variables and the inverse variance method for continuous variables, and pooled using a random or fixed effects model depending on heterogeneity. RESULTS: Twelve trials were included in the analysis. Eight involved sulodexide while two each involved low molecular weight heparin and danaparoid. We found no statistically significant difference between the heparinoid and placebo groups for all-cause mortality (95% CI, HR 0.79 [0.41, 1.53], p=0.49), number of patients reaching therapeutic success (95% CI, OR 0.97 [0.71, 1.33], p=0.87), serum creatinine (95% CI, MD 2.55 umol/L [-0.54, 5.65], p=0.11), and creatinine clearance (95% CI, MD -8.55 mg/min [-18.28, 1.18], p=0.09). We also found no statistically significant difference in urinary albumin excretion rate (UAER) between Type 2 heparinoid-treated DKD patients compared to placebo (95% CI, log transformed MD 0.13 mg/24h [-0.42, 0.68], p=0.65); however, a statistically significant UAER reduction was seen in Type 1 heparinoid-treated DKD patients compared to placebo (95% CI, log-transformed MD -1.5 mg/24h [-2.79, -0.21], p=0.02). This subgroup analysis was performed due to initial heterogeneity (I2=57%). CONCLUSION: Heparinoid supplementation was not associated with statistically significant changes in Type 2 DM patients. However, it may be associated with a statistically significant UAER reduction of approximately 31.62 mg/24 h as compared to placebo in Type 1 DM patients. Due to sparse data on hard clinical outcomes, larger studies are recommended.