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Aims/introduction: Deficiency of neurotropic factors is implicated in diabetic neuropathy (DN). Netrin-1 is a neurotropic factor, but its association with DN has not been explored. We have assessed the association between serum netrin-1 levels and early diabetic neuropathy assessed by quantifying corneal nerve fiber loss using corneal confocal microscopy., Materials and Methods: A total of 72 participants with type 2 diabetes, without and with corneal nerve fiber loss (DN- n = 42, DN+ n = 30), and 45 healthy controls were studied. Serum netrin-1 levels were measured by enzyme-linked immunosorbent assay, and corneal nerve morphology was assessed using corneal confocal microscopy., Results: Corneal nerve fiber density, branch density, fiber length and serum netrin-1 levels were significantly lower in the DN- and DN+ groups compared with controls (P < 0.001). Netrin-1 levels correlated with corneal nerve fiber length in the DN+ group (r = 0.51; P < 0.01). A receiver operating characteristic curve analysis showed that a netrin-1 cut-off value of 599.6 (pg/mL) had an area under the curve of 0.85, with a sensitivity of 76% and specificity of 74% (P < 0.001; 95% confidence interval 0.76-0.94) for differentiating patients with and without corneal nerve loss., Conclusions: Serum netrin-1 levels show a progressive decline with increasing severity of small nerve fiber damage in patients with diabetes. Netrin-1 could act as a biomarker for small nerve fiber damage in DN., (© 2024 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aim: To assess the impact of insulin glargine (100 U/mL) and lixisenatide (iGlarLixi) fixed-ratio combination therapy on the overall management of glycaemia in patients with type 2 diabetes (T2D), previously inadequately controlled with oral antidiabetic drugs ± basal insulin or glucagon-like peptide-1 receptor agonists (GLP-1 RAs)., Materials and Methods: This 12-month, international, multicentre, prospective, observational study included patients (age ≥ 18 years) with T2D who had initiated iGlarLixi within 1 month prior to study inclusion. Data were collected at study inclusion, month 3, month 6 and month 12 from patient diaries, self-measured plasma glucose, and questionnaires. The primary endpoint was change in HbA1c from baseline to month 6., Results: Of the 737 eligible participants (mean age: 57.8 [standard deviation: 11.2] years; male: 49%), 685 had baseline and post-baseline HbA1c data available. The least squares mean change in HbA1c from baseline to month 6 was -1.4% (standard error [95% confidence interval (CI)]: 0.05 [-1.5, -1.3]). The absolute change from baseline at month 12 was -1.7% ± 1.9% (95% CI: -1.9, -1.5). There were 72 hypoglycaemia events reported during the study period, with a very low incidence of severe hypoglycaemia (two participants [rate: 0.003 events per patient-year])., Conclusions: This real-world observational study shows that initiation of iGlarLixi in people with T2D inadequately controlled on oral antidiabetic drugs ± basal insulin or GLP-1 RAs improves glycaemic control with a low incidence of hypoglycaemia., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Diabetes is recognized as a risk factor for cognitive decline, but the underlying mechanisms remain elusive. We aimed to identify the metabolic pathways altered in diabetes-associated cognitive decline (DACD) using untargeted metabolomics. We conducted liquid chromatography-mass spectrometry-based untargeted metabolomics to profile serum metabolite levels in 100 patients with type 2 diabetes (T2D) (54 without and 46 with DACD). Multivariate statistical tools were used to identify the differentially expressed metabolites (DEMs), and enrichment and pathways analyses were used to identify the signaling pathways associated with the DEMs. The receiver operating characteristic (ROC) analysis was employed to assess the diagnostic accuracy of a set of metabolites. We identified twenty DEMs, seven up- and thirteen downregulated in the DACD vs. DM group. Chemometric analysis revealed distinct clustering between the two groups. Metabolite set enrichment analysis found significant enrichment in various metabolite sets, including galactose metabolism, arginine and unsaturated fatty acid biosynthesis, citrate cycle, fructose and mannose, alanine, aspartate, and glutamate metabolism. Pathway analysis identified six significantly altered pathways, including arginine and unsaturated fatty acid biosynthesis, and the metabolism of the citrate cycle, alanine, aspartate, glutamate, a-linolenic acid, and glycerophospholipids. Classifier models with AUC-ROC > 90% were developed using individual metabolites or a combination of individual metabolites and metabolite ratios. Our study provides evidence of perturbations in multiple metabolic pathways in patients with DACD. The distinct DEMs identified in this study hold promise as diagnostic biomarkers for DACD patients.

Objective: To assess if optical coherence tomography (OCT) and OCT angiography (OCTA) measures are associated with the development and worsening of diabetic retinopathy (DR) over four years., Methods: 280 participants with type 2 diabetes underwent ultra-wide field fundus photography, OCT and OCTA. OCT-derived macular thickness measures, retinal nerve fibre layer and ganglion cell-inner plexiform layer thickness and OCTA-derived foveal avascular zone area, perimeter, circularity, vessel density (VD) and macular perfusion (MP) were examined in relation to the development and worsening of DR over four years., Results: After four years, 206 eyes of 219 participants were eligible for analysis. 27 of the 161 eyes (16.7%) with no DR at baseline developed new DR, which was associated with a higher baseline HbA 1c and longer diabetes duration. Of the 45 eyes with non-proliferative DR (NPDR) at baseline, 17 (37.7%) showed DR progression. Baseline VD (12.90 vs. 14.90 mm/mm 2 , p = 0.032) and MP (31.79% vs. 36.96%, p = 0.043) were significantly lower in progressors compared to non-progressors. Progression of DR was inversely related to VD ((hazard ratio [HR] = 0.825) and to MP (HR = 0.936). The area under the receiver operating characteristic curves for VD was AUC = 0.643, with 77.4% sensitivity and 41.8% specificity for a cut-off of 15.85 mm/mm 2 and for MP it was AUC = 0.635, with 77.4% sensitivity and 25.5% specificity for a cut-off of 40.8%., Conclusions: OCTA metrics have utility in predicting progression rather than the development of DR in individuals with type 2 diabetes., (© 2023. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Background: Bardet-Biedl syndrome (BBS) is an autosomal recessive, genetically heterogeneous, pleiotropic disorder caused by variants in genes involved in the function of the primary cilium. We have harnessed genomics to identify BBS and ophthalmic technologies to describe novel features of BBS., Case Presentation: A patient with an unclear diagnosis of syndromic type 2 diabetes mellitus, another affected sibling and unaffected siblings and parents were sequenced using DNA extracted from saliva samples. Corneal confocal microscopy (CCM) and retinal spectral domain optical coherence tomography (SD-OCT) were used to identify novel ophthalmic features in these patients. The two affected individuals had a homozygous variant in C8orf37 (p.Trp185*). SD-OCT and CCM demonstrated a marked and patchy reduction in the retinal nerve fiber layer thickness and loss of corneal nerve fibers, respectively., Conclusion: This report highlights the use of ophthalmic imaging to identify novel retinal and corneal abnormalities that extend the phenotype of BBS in a patient with syndromic type 2 diabetes., (© 2023. The Author(s).)

Aims/hypothesis: Insulin is the primary treatment for type 1 diabetes. However, alternative glucose-lowering therapies are used adjunctively, but importantly are off-label in type 1 diabetes. Little work has previously been undertaken to evaluate safety with long-term efficacy and cardio-renal benefits of such therapies. We sought to investigate the real-world impact of sodium-glucose cotransporter 2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy in individuals with type 1 diabetes in relation to effect on blood glucose levels, adverse events and cardio-renal outcomes., Methods: We performed a retrospective cohort study of all patients aged 18 or over with type 1 diabetes on the TriNetX platform, a global collaborative network providing access to real-time, anonymised medical records. We included patients who had been treated with an SGLT2i or GLP-1 RA for at least 6 months and analysed the efficacy, safety and cardio-renal outcomes 5 years after initiation of therapy., Results: We identified 196,691 individuals with type 1 diabetes, 13% of whom were treated with adjunctive glucose-lowering therapy in addition to insulin. Included in the core analysis were 1822 patients treated with a GLP-1 RA and 992 individuals treated with an SGLT2i. Both agents provided clinically meaningful reductions in HbA 1c (-2.6 mmol/mol [-0.2%] with SGLT2i and -5.4 mmol/mol [-0.5%] with GLP-1 RA). The SGLT2i treated cohort showed preservation of eGFR over a 5-year period compared with the GLP-1 RA treated cohort (+3.5 ml/min per 1.73 m 2 vs -7.2 ml/min per 1.73 m 2 , respectively), including patients with established chronic kidney disease (CKD). The SGLT2i treated cohort experienced higher rates of diabetic ketoacidosis (DKA) (RR 2.08 [95% CI 1.05, 4.12] p=0.0309) and urinary tract infection/pyelonephritis (RR 2.27 [95% CI 1.12, 4.55] p=0.019) compared with the GLP-1 RA treated cohort. However, the SGLT2i treated cohort were less likely to develop heart failure (RR 0.44 [95% CI 0.23, 0.83] p=0.0092), CKD (RR 0.49 [95% CI 0.28, 0.86] p=0.0118) and be hospitalised for any cause (RR 0.59 [95% CI 0.46, 0.76] p≤0.0001) when compared with the GLP-1 RA treated cohort., Conclusions/interpretation: Both SGLT2is and GLP-1 RAs have potential benefits as adjunctive agents in type 1 diabetes. SGLT2is provide cardio-renal benefits, despite an increase in the risk of DKA and urinary tract infection compared with GLP-1 RA therapy. Long-term evaluation of the efficacy and safety of these adjunctive therapies is required to guide their use in individuals with type 1 diabetes., (© 2023. The Author(s).)

Bariatric surgery in people with obesity can lead to long-term remission of type 2 diabetes mellitus (T2DM) and a reduction in the incidence of macrovascular complications. The impact of bariatric surgery on microvascular complications is less clear. In this narrative review, we sought to evaluate the effect of bariatric surgery on microvascular complications in patients with and without diabetes. The risk of developing microvascular complications is increased in people with obesity, and this is amplified in those with T2DM. The impact of metabolic surgery on microvascular complications is limited to a subgroup analysis of studies or statistical modeling to predict the glycemia-independent effect of bariatric surgery. While bariatric surgery halts the progression of retinopathy in those with minimal retinopathy, it may worsen in those with advanced retinopathy. Bariatric surgery improves proteinuria and major renal outcomes, regardless of the severity of renal impairment. Bariatric surgery in patients with obesity with or without diabetes is associated with an improvement in neuropathic symptoms and regeneration of small nerve fibers. In conclusion, bariatric surgery is associated with an improvement in microvascular complications. Further studies are needed to elucidate the underlying mechanisms for the favorable effect of bariatric surgery on microvascular outcomes., (© 2023 World Obesity Federation.)

Aim: To compare the efficacy and safety of insulin glargine-300 once daily (Gla-300) with insulin degludec/aspart (IDegAsp) once daily in patients with type 2 diabetes (T2D) inadequately controlled on oral anti-diabetic drugs (OADs)., Materials and Methods: A systematic literature review of randomized controlled trials was followed by an indirect treatment comparison of studies involving insulin naïve adults, inadequately controlled [glycated haemoglobin (HbA1c) ≥7.0%] on OADs, who received Gla-300 or IDegAsp once daily. Outcomes of interest were change in HbA1c, blood glucose, weight and insulin dose, as well as incidence and event rate of hypoglycaemia and other adverse events., Results: Four trials with broadly similar baseline patient characteristics were included in the meta-analyses and indirect treatment comparison. At 24-28 weeks, the indirect comparison of Gla-300 to IDegAsp once daily estimated no statistically significant difference for change in HbA1c (%) from baseline [mean difference of 0.10% (95% CI: -0.20, 0.39; p = .52)]; a statistically significant mean difference of -1.31 kg (95% CI: -1.97, -0.65; p < .05) for change in body weight from baseline; statistically significant odds ratios of 0.62 (95% CI: 0.41, 0.93; p < .05) for incidence of any hypoglycaemia; and 0.47 (95% CI: 0.25, 0.87; p < .05) for incidence of anytime confirmed hypoglycaemia (plasma glucose <3.0-3.1 mmol/L). No significant differences were observed for insulin dose and adverse events., Conclusion: In insulin-naïve patients with T2D inadequately controlled on OADs, commencing Gla-300 shows a comparable HbA1c reduction, but with significantly less weight gain and a lower incidence of any and confirmed hypoglycaemia compared with commencing IDegAsp., (© 2023 Sanofi and The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: Cardiac autonomic neuropathy (CAN) has been suggested to be associated with hypoglycemia and impaired hypoglycemia unawareness. We have assessed the relationship between CAN and extensive measures of glucose variability (GV) in patients with type 1 and type 2 diabetes., Methods: Participants with diabetes underwent continuous glucose monitoring (CGM) to obtain measures of GV and the extent of hyperglycemia and hypoglycemia and cardiovascular autonomic reflex testing., Results: Of the 40 participants (20 T1DM and 20 T2DM) (aged 40.70 ± 13.73 years, diabetes duration 14.43 ± 7.35 years, HbA1c 8.85 ± 1.70%), 23 (57.5%) had CAN. Despite a lower coefficient of variation (CV) (31.26 ± 11.87 vs. 40.33 ± 11.03, P = 0.018), they had a higher CONGA (8.42 ± 2.58 vs. 6.68 ± 1.88, P = 0.024) with a lower median LBGI (1.60 (range: 0.20-3.50) vs. 4.90 (range: 3.20-7.40), P = 0.010) and percentage median time spent in hypoglycemia (4 (range:4-13) vs. 1 (range:0-5), P = 0.008), compared to those without CAN. The percentage GRADE Euglycemia (3.30 ± 2.78 vs. 5.69 ± 3.09, P = 0.017) and GRADE Hypoglycemia (0.3 (range: 0 - 3.80) vs. 1.8 (range: 0.9-6.5), P = 0.036) were significantly lower, while the percentage median GRADE Hyperglycemia (95.45 (range:93-98) vs. 91.6 (82.8-95.1), P = 0.013) was significantly higher in participants with CAN compared to those without CAN., Conclusion: CAN was associated with increased glycemic variability with less time in euglycemia attributed to a greater time in hyperglycemia but not hypoglycemia., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: To investigate the epidemiology and clinical management of patients with type 2 diabetes (T2D) and established atherosclerotic cardiovascular disease (eASCVD) or high/very high ASCVD risk, defined by the 2021 European Society of Cardiology Guidelines, in seven countries in the Middle East and Africa (PACT-MEA; NCT05317845), and to assess physicians' attitudes and the basis for their decision-making in the management of these patients., Materials and Methods: PACT-MEA is a cross-sectional, observational study undertaken in Bahrain, Egypt, Jordan, Kuwait, Qatar, South Africa and the United Arab Emirates based on a medical chart review of approximately 3700 patients with T2D in primary and secondary care settings, and a survey of approximately 400 physicians treating patients with T2D., Results: The primary and secondary objectives are to determine the prevalence of eASCVD and high/very high ASCVD risk in patients with T2D. Current treatment with cardioprotective antidiabetic medication, the proportion of patients meeting the treatment criteria for reimbursement in the study countries where there is an applicable reimbursement guideline, and physician-reported factors in clinical decision-making in T2D management, will also be assessed., Conclusions: This large cross-sectional study will establish the estimated prevalence and management of eASCVD and high/very high ASCVD risk in patients with type 2 diabetes across the Middle East and Africa., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: To explore if novel non-invasive diagnostic technologies identify early small nerve fibre and retinal neurovascular pathology in prediabetes., Methods: Participants with normoglycaemia, prediabetes or type 2 diabetes underwent an exploratory cross-sectional analysis with optical coherence tomography angiography (OCT-A), handheld electroretinography (ERG), corneal confocal microscopy (CCM) and evaluation of electrochemical skin conductance (ESC)., Results: Seventy-five participants with normoglycaemia (n = 20), prediabetes (n = 29) and type 2 diabetes (n = 26) were studied. Compared with normoglycaemia, mean peak ERG amplitudes of retinal responses at low (16-Td·s: 4.05 μV, 95% confidence interval [95% CI] 0.96-7.13) and high (32-Td·s: 5·20 μV, 95% CI 1.54-8.86) retinal illuminance were lower in prediabetes, as were OCT-A parafoveal vessel densities in superficial (0.051 pixels/mm 2 , 95% CI 0.005-0.095) and deep (0.048 pixels/mm 2 , 95% CI 0.003-0.093) retinal layers. There were no differences in CCM or ESC measurements between these two groups. Correlations between HbA 1c and peak ERG amplitude at 32-Td·s (r = -0.256, p = 0.028), implicit time at 32-Td·s (r = 0.422, p < 0.001) and 16-Td·s (r = 0.327, p = 0.005), OCT parafoveal vessel density in the superficial (r = -0.238, p = 0.049) and deep (r = -0.3, p = 0.017) retinal layers, corneal nerve fibre length (CNFL) (r = -0.293, p = 0.017), and ESC-hands (r = -0.244, p = 0.035) were observed. HOMA-IR was a predictor of CNFD (β = -0.94, 95% CI -1.66 to -0.21, p = 0.012) and CNBD (β = -5.02, 95% CI -10.01 to -0.05, p = 0.048)., Conclusions: The glucose threshold for the diagnosis of diabetes is based on emergent retinopathy on fundus examination. We show that both abnormal retinal neurovascular structure (OCT-A) and function (ERG) may precede retinopathy in prediabetes, which require confirmation in larger, adequately powered studies., (© 2022 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Type 2 diabetes (T2D) has a heterogeneous etiology influencing its progression, treatment, and complications. A data driven cluster analysis in European individuals with T2D previously identified four subtypes: severe insulin deficient (SIDD), severe insulin resistant (SIRD), mild obesity-related (MOD), and mild age-related (MARD) diabetes. Here, the clustering approach was applied to individuals with T2D from the Qatar Biobank and validated in an independent set. Cluster-specific signatures of circulating metabolites and proteins were established, revealing subtype-specific molecular mechanisms, including activation of the complement system with features of autoimmune diabetes and reduced 1,5-anhydroglucitol in SIDD, impaired insulin signaling in SIRD, and elevated leptin and fatty acid binding protein levels in MOD. The MARD cluster was the healthiest with metabolomic and proteomic profiles most similar to the controls. We have translated the T2D subtypes to an Arab population and identified distinct molecular signatures to further our understanding of the etiology of these subtypes., (© 2022. The Author(s).)

Aims: To assess the clinical characteristics and outcomes of patients hospitalized with DKA., Methods: We examined the hospital database for patients admitted with DKA to all government hospitals in Qatar over 6 years., Results: We evaluated a total of 1330 patients [(37.3 % with type 1 diabetes (T1DM) and 62.7 % with type 2 diabetes (T2DM)] with 1613 episodes of DKA. Patients with T2DM were older than those with T1DM [48.0 (38.0-60.0), 26.0 (21.0-31.0) years] while there was no difference in DKA severity and laboratory values on admission or time to resolution of DKA. Admission to the intensive care unit was higher (38.9 % vs. 26.6 %; P < 0.001) with a longer hospital stay [5 (2.0-9.0) vs. 2 (2.0-4.0) days, P < 0.001] and markedly higher mortality (7.4 % vs. 1 %; P < 0.001) in patients with T2DM compared to T1DM. On multivariable logistic regression analysis, significant predictors of mortality were older age (odds ratio, 1.11; 95 % CI, 1.07-1.15; P = 0.0001), and admission to the intensive care unit (odds ratio, 3.61; 95 % CI, 1.69-7.72;P = 0.001)., Conclusion: In this national cohort of patients hospitalized with DKA, those with T2DM had a 7-fold increase in inpatient mortality associated with older age and admission to the intensive care unit., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims/introduction: Limited studies have identified risk factors linked to the progression of diabetic peripheral neuropathy (DPN) in type 2 diabetes. This study examined the association of risk factors with change in neuropathy measures over 2 years., Materials and Methods: Participants with type 2 diabetes (n = 78) and controls (n = 26) underwent assessment of clinical and metabolic parameters and neuropathy using corneal confocal microscopy (CCM), vibration perception threshold (VPT), and the DN4 questionnaire at baseline and 2 year follow-up., Results: Participants with type 2 diabetes had a lower corneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) (P ≤ 0.0001) and a higher VPT (P ≤ 0.01) compared with controls. Over 2 years, despite a modest reduction in HbA1c (P ≤ 0.001), body weight (P ≤ 0.05), and LDL (P ≤ 0.05) the prevalence of DPN (P = 0.28) and painful DPN (P = 0.21) did not change, but there was a significant further reduction in CNBD (P ≤ 0.0001) and CNFL (P ≤ 0.05). CNFD, CNBD, and CNFL decreased significantly in physically inactive subjects (P < 0.05-0.0001), whilst there was no change in CNFD (P = 0.07) or CNFL (P = 0.85) in physically active subjects. Furthermore, there was no change in CNFD (P = 0.82), CNBD (P = 0.08), or CNFL (P = 0.66) in patients treated with glucose lowering medication associated with weight loss, whilst CNBD (P = 0.001) decreased in patients on glucose lowering medication associated with weight gain., Conclusions: In participants with type 2 diabetes, despite a modest improvement in HbA1c, body weight, and LDL there was a progressive loss of corneal nerve fibers; except in those who were physically active or on glucose lowering medication associated with weight loss., (© 2022 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Objective: To examine the relationship of visual function as assessed by visual acuity, contrast sensitivity, and multifocal electroretinography (mfERG) to macular structural and microvascular measures on optical coherence tomography (OCT) and angiography (OCTA) in individuals with diabetes., Methods: This is a prospective observational study conducted at a tertiary eye care centre in India. Right eyes of 121 adults with type 2 diabetes with no diabetic retinopathy (DR), mild or moderate nonproliferative DR (NPDR) were examined. Severe NPDR, proliferative DR and diabetic macular oedema were excluded. Participants underwent assessment of glycated haemoglobin (HbA 1C ), blood pressure, best corrected visual acuity (LogMAR), contrast sensitivity (CS), mfERG, ultrawide field fundus photography, OCT and OCTA. Correlations were assessed by Spearman's rank correlation (rho)., Results: Of the total of 121 eyes, 89 had No DR, 32 had mild to moderate NPDR. In the No DR group, the LogMAR acuity was significantly and negatively correlated to central subfoveal thickness (CST) (rho = -0.420), macular vessel density (rho = -0.270) and perfusion (rho = -0.270). (ii) Contrast sensitivity correlated to foveal avascular zone circularity (rho = 0.297); (iii) mfERG P1 response densities were better with higher macular perfusion index (rho = 0.240). In the NPDR group, the LogMAR acuity also showed a significant negative correlation to CST (rho = -0.379). Other correlations were not significant., Conclusion: Retinal and visual functional changes are evident in diabetic patients with No DR and are correlated to subclinical retinal structural changes detectable using multimodal imaging., (© 2021. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Aims/introduction: This study determined the prevalence and risk factors for diabetic peripheral neuropathy (DPN), painful DPN and diabetic foot ulceration (DFU) in patients with type 2 diabetes in secondary healthcare in Qatar, Kuwait and the Kingdom of Saudi Arabia., Materials and Methods: Adults aged 18-85 years with type 2 diabetes were randomly enrolled from secondary healthcare, and underwent clinical and metabolic assessment. DPN was evaluated using vibration perception threshold and neuropathic symptoms and painful Diabetic Peripheral Neuropathy was evaluated using the Douleur Neuropathique 4 questionnaire., Results: A total of 3,021 individuals were recruited between June 2017 and May 2019. The prevalence of DPN was 33.3%, of whom 52.2% were at risk of DFU and 53.6% were undiagnosed. The prevalence of painful DPN was 43.3%, of whom 54.3% were undiagnosed. DFU was present in 2.9%. The adjusted odds ratios for DPN and painful DPN were higher with increasing diabetes duration, obesity, poor glycemic control and hyperlipidemia, and lower with greater physical activity. The adjusted odds ratio for DFU was higher with the presence of DPN, severe loss of vibration perception, hypertension and vitamin D deficiency., Conclusions: This is the largest study to date from the Middle East showing a high prevalence of undiagnosed DPN, painful DPN and those at risk of DFU in patients with type 2 diabetes, and identifies their respective risk factors., (© 2022 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

To examine the retinal structure and function in relation to diabetes duration and glycemia in patients without diabetic retinopathy (DR). 85 adults with type 2 diabetes without DR or macular edema underwent dilated indirect ophthalmoscopy, optical coherence tomography (OCT), ultra-wide field fundus photography, multifocal electroretinography (mfERG) and HbA 1C assessment. Patients were stratified as those with diabetes duration < 10 years and ≥ 10 years. Right eyes of all participants were analyzed. mfERG was analysed as ring 12, 34, 56. No significant differences were noted in OCT-derived retinal thickness measures between groups. mfERG P1 latencies were delayed, and amplitudes (nV/deg 2 ) were reduced in all three rings in those with diabetes duration ≥ 10 years vs. < 10 years, with significant correlations to diabetes duration in all rings. Logistic regression showed that duration of diabetes ≥ 10 years was associated with greater age (odds ratio (OR) 1.081, 95% CI 1.022, 1.143) and lower P1 amplitudes in the middle ring (OR 0.924, 95% CI 0.854, 0.999). No significant correlations were observed between HbA 1c and retinal measures. In the absence of DR, early retinal functional alterations are detectable on mfERG in patients with longer diabetes duration, but with no difference in OCT-derived retinal thickness., (© 2022. The Author(s).)

Aims/introduction: Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) improve glycemic control and weight, but might be associated with dehydration, hypotension and ketoacidosis, especially in patients with type 2 diabetes mellitus who fast during Ramadan. This meta-analysis evaluates the effects of Ramadan fasting on patients with type 2 diabetes mellitus treated with SGLT-2i., Materials and Methods: A literature search was carried out in PubMed, Embase and the Cochrane Library. Quality assessment was carried out using the ROBINS-I and Cochrane tools for risk of bias, and analyses were carried out using RevMan version 5.3., Results: A total of five studies were included in this meta-analysis. During Ramadan, there was a significant reduction in glycated hemoglobin (P < 0.00001) and diastolic blood pressure (P = 0.006), with a non-significant trend for a reduction in weight (P = 0.44) and systolic blood pressure (P = 0.67). The number and severity of hypoglycemic episodes was lower in patients with type 2 diabetes mellitus treated with SGLT-2i compared with sulfonylureas. There was no significant change in estimated glomerular filtration rate, β-hydroxybutyrate, bicarbonate or anion gap. However, we identified considerable heterogeneity among studies, and a lack of head-to-head studies with structured outcome reporting on the risks and benefits of SGLT-2i during Ramadan., Conclusions: This systematic review and meta-analysis shows that patients with type 2 diabetes treated with SGLT2i's during Ramadan have an improvement in HbA1c, less hypoglycemia and no major adverse effects., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background and Aims: The causal relationship between LDL cholesterol (LDL-C) and the pathogenesis of atherosclerosis is well established. Previous studies have shown that modifications, glycation and oxidation of LDL enhance its atherogenic potential. Glycation of LDL occurs in it is main protein component, apolipoprotein B100 (ApoB). Our aim was to assess the effect of bariatric surgery on circulating glycApoB levels and understand the factors influencing changes in its circulating levels., Methods: We measured glycApoB in 49 individuals before, 6 and 12 months after bariatric surgery. We also assessed clinical parameters, lipoproteins, markers of inflammation and glycaemia. Correlation analysis was done to understand associations between changes in variables from baseline to 12 months after surgery., Results: Reductions in glycApoB post-bariatric surgery were significant regardless of whether the patients suffered from type 2 diabetes (T2DM) or took lipid-lowering therapy. There were no significant differences in glycApoB levels at baseline and follow-up between participants with T2DM and those without. GlycApoB declined from baseline in non-diabetics at 6 months and significantly at 12 months (1.09 mg/l vs 0.63 mg/l vs 0.49 mg/l, p < 0.05), and in those with T2DM at 6 months and significantly at 12 months (1.77 mg/l vs 1.03 mg/l vs 0.68 mg/l, p < 0.05). The percentage change in glycApoB correlated (p < 0.05) with changes in glucose (ρ = 0.40), insulin (ρ = 0.41) and HOMA-IR (%) (ρ = 0.43). There were no significant associations between changes in glycApoB and changes in total serum ApoB, LDL-C, high sensitivity C-reactive protein, weight, or BMI., Conclusions: Bariatric surgery reduces levels of glycApoB; this reduction is associated with decreased insulin resistance postoperatively. This potentially reflects the potent influence of obesity-related insulin resistance on lipoprotein glycation. Our observations are of potential importance in explaining the effectiveness of bariatric surgery in decreasing cardiovascular disease (CVD) risk in both T2DM and obese individuals without T2DM, as glycation of ApoB is known to be associated with increased atherogenesis., (Copyright © 2022. Published by Elsevier B.V.)

Aims/hypothesis: We aimed to develop an artificial intelligence (AI)-based deep learning algorithm (DLA) applying attribution methods without image segmentation to corneal confocal microscopy images and to accurately classify peripheral neuropathy (or lack of)., Methods: The AI-based DLA utilised convolutional neural networks with data augmentation to increase the algorithm's generalisability. The algorithm was trained using a high-end graphics processor for 300 epochs on 329 corneal nerve images and tested on 40 images (1 image/participant). Participants consisted of healthy volunteer (HV) participants (n = 90) and participants with type 1 diabetes (n = 88), type 2 diabetes (n = 141) and prediabetes (n = 50) (defined as impaired fasting glucose, impaired glucose tolerance or a combination of both), and were classified into HV, those without neuropathy (PN-) (n = 149) and those with neuropathy (PN+) (n = 130). For the AI-based DLA, a modified residual neural network called ResNet-50 was developed and used to extract features from images and perform classification. The algorithm was tested on 40 participants (15 HV, 13 PN-, 12 PN+). Attribution methods gradient-weighted class activation mapping (Grad-CAM), Guided Grad-CAM and occlusion sensitivity displayed the areas within the image that had the greatest impact on the decision of the algorithm., Results: The results were as follows: HV: recall of 1.0 (95% CI 1.0, 1.0), precision of 0.83 (95% CI 0.65, 1.0), F 1 -score of 0.91 (95% CI 0.79, 1.0); PN-: recall of 0.85 (95% CI 0.62, 1.0), precision of 0.92 (95% CI 0.73, 1.0), F 1 -score of 0.88 (95% CI 0.71, 1.0); PN+: recall of 0.83 (95% CI 0.58, 1.0), precision of 1.0 (95% CI 1.0, 1.0), F 1 -score of 0.91 (95% CI 0.74, 1.0). The features displayed by the attribution methods demonstrated more corneal nerves in HV, a reduction in corneal nerves for PN- and an absence of corneal nerves for PN+ images., Conclusions/interpretation: We demonstrate promising results in the rapid classification of peripheral neuropathy using a single corneal image. A large-scale multicentre validation study is required to assess the utility of AI-based DLA in screening and diagnostic programmes for diabetic neuropathy., (© 2021. The Author(s).)

Purpose: To examine (i) the retinal structure and function using optical coherence tomography angiography (OCTA) and multifocal electroretinography (mfERG), respectively, in eyes with and without nonproliferative diabetic retinopathy (NPDR), (ii) and their interrelationship between retinal structure (OCTA) and function (mfERG) in the two groups independently., Methods: This was a prospective observational study. One hundred twenty-one eligible participants with type 2 diabetes with No DR (n = 89), or with mild or moderate NPDR (n = 32) underwent ophthalmic examination, ultrawide field-view fundus photography, OCTA, and mfERG. Group differences were assessed using a Mann-Whitney U test. Correlations were assessed using Spearman's rho., Results: There were no significant differences in OCTA measures between the two groups. The mfERG P1 implicit times (rings 1-6) were significantly delayed and P1 response densities in rings 5 and 6 were significantly lower in participants with NPDR compared to those with No DR. In those with No DR, P1 implicit times in almost all rings were delayed in relation to lower vessel density and perfusion (maximum variance noted was 13%). In individuals with NPDR, the P1 response density in rings 2 and 3 showed a positive nonsignificant correlation with macular perfusion., Conclusion: In those with diabetes with No DR, retinal neuronal function is influenced by lower macular vessel density and perfusion. The retinal neuronal function is abnormal in individuals with NPDR compared to those with No DR and is not correlated with OCT angiometric measures, suggesting the likelihood of a different retinal structural correlate., Competing Interests: None

Aims/introduction: This study aimed to investigate whether insulin resistance (IR) in individuals with type 2 diabetes undergoing intensive glycemic control determines the extent of improvement in neuropathy., Materials and Methods: This was an exploratory substudy of an open-label, randomized controlled trial of individuals with poorly controlled type 2 diabetes treated with exenatide and pioglitazone or insulin to achieve a glycated hemoglobin <7.0% (<53 mmol/mol). Baseline IR was defined using homeostasis model assessment of IR, and change in neuropathy was assessed using corneal confocal microscopy., Results: A total of 38 individuals with type 2 diabetes aged 50.2 ± 8.5 years with (n = 25, 66%) and without (n = 13, 34%) IR were studied. There was a significant decrease in glycated hemoglobin (P < 0.0001), diastolic blood pressure (P < 0.0001), total cholesterol (P < 0.01) and low-density lipoprotein (P = 0.05), and an increase in bodyweight (P < 0.0001) with treatment. Individuals with homeostasis model assessment of IR <1.9 showed a significant increase in corneal nerve fiber density (P ≤ 0.01), length (P ≤ 0.01) and branch density (P ≤ 0.01), whereas individuals with homeostasis model assessment of IR ≥1.9 showed no change. IR was negatively associated with change in corneal nerve fiber density after adjusting for change in bodyweight (P < 0.05)., Conclusions: Nerve regeneration might be limited in individuals with type 2 diabetes and IR undergoing treatment with pioglitazone plus exenatide or insulin to improve glycemic control., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Objective: Corneal nerve fiber length (CNFL) has been shown in research studies to identify diabetic peripheral neuropathy (DPN). In this longitudinal diagnostic study, we assessed the ability of CNFL to predict the development of DPN., Research Design and Methods: From a multinational cohort of 998 participants with type 1 and type 2 diabetes, we studied the subset of 261 participants who were free of DPN at baseline and completed at least 4 years of follow-up for incident DPN. The predictive validity of CNFL for the development of DPN was determined using time-dependent receiver operating characteristic (ROC) curves., Results: A total of 203 participants had type 1 and 58 had type 2 diabetes. Mean follow-up time was 5.8 years (interquartile range 4.2-7.0). New-onset DPN occurred in 60 participants (23%; 4.29 events per 100 person-years). Participants who developed DPN were older and had a higher prevalence of type 2 diabetes, higher BMI, and longer duration of diabetes. The baseline electrophysiology and corneal confocal microscopy parameters were in the normal range but were all significantly lower in participants who developed DPN. The time-dependent area under the ROC curve for CNFL ranged between 0.61 and 0.69 for years 1-5 and was 0.80 at year 6. The optimal diagnostic threshold for a baseline CNFL of 14.1 mm/mm 2 was associated with 67% sensitivity, 71% specificity, and a hazard ratio of 2.95 (95% CI 1.70-5.11; P < 0.001) for new-onset DPN., Conclusions: CNFL showed good predictive validity for identifying patients at higher risk of developing DPN ∼6 years in the future., (© 2021 by the American Diabetes Association.)

Aims/introduction: Painful diabetic peripheral neuropathy (pDPN) is associated with small nerve fiber degeneration and regeneration. This study investigated whether the presence of pDPN might influence nerve regeneration in patients with type 2 diabetes undergoing intensive glycemic control., Materials and Methods: This exploratory substudy of an open-label randomized controlled trial undertook the Douleur Neuropathique en 4 questionnaire and assessment of electrochemical skin conductance, vibration perception threshold and corneal nerve morphology using corneal confocal microscopy in participants with and without pDPN treated with exenatide and pioglitazone or basal-bolus insulin at baseline and 1-year follow up, and 18 controls at baseline only., Results: Participants with type 2 diabetes, with (n = 13) and without (n = 28) pDPN had comparable corneal nerve fiber measures, electrochemical skin conductance and vibration perception threshold at baseline, and pDPN was not associated with the severity of DPN. There was a significant glycated hemoglobin reduction (P < 0.0001) and weight gain (P < 0.005), irrespective of therapy. Participants with pDPN showed a significant increase in corneal nerve fiber density (P < 0.05), length (P < 0.0001) and branch density (P < 0.005), and a decrease in the Douleur Neuropathique en 4 score (P < 0.01), but no change in electrochemical skin conductance or vibration perception threshold. Participants without pDPN showed a significant increase in corneal nerve branch density (P < 0.01) and no change in any other neuropathy measures. A change in the severity of painful symptoms was not associated with corneal nerve regeneration and medication for pain., Conclusions: This study showed that intensive glycemic control is associated with greater corneal nerve regeneration and an improvement in the severity of pain in patients with painful diabetic neuropathy., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: Diabetic microvascular complications are a major cause of morbidity and are related to glycaemic control and cardiovascular risk factors., Aims: We sought to determine the association of microvascular complications in relation to control of glycemia, blood pressure and lipids in T2DM patients attending secondary care in Qatar., Methods: This is a cross-sectional study undertaken in patients with T2DM attending Qatar's National Diabetes Centres. Patients underwent assessment of glycemia, blood pressure and lipids and prevalence of diabetic peripheral neuropathy (DPN), retinopathy and microalbuminuria., Results: We included 1114 subjects aged 52.1 ± 11.3 years with a duration of diabetes 10.0 ± 7.6 years and had a prevalence of 25.8% for DPN, 34.3% for painful DPN, 36.8% for microalbuminuria and 25.1% for retinopathy. Patients who achieved an HbA1c ≤ 7.0% compared to >7% had a significantly lower prevalence of DPN (P < 0.01), painful DPN (P < 0.01), retinopathy (P < 0.01) and microalbuminuria (P < 0.007). Patients who achieved a systolic BP ≤ 140 mmHg compared to >140 mmHg had a significantly lower prevalence of DPN (P < 0.001), painful DPN (P < 0.001), retinopathy (P < 0.001) and microalbuminuria (P < 0.001). Patients who achieved an LDL ≤2.6 mmol/l compared to >2.6 mmol/l had a significantly higher prevalence of DPN (P < 0.03), but no difference in other outcomes. There was no difference in microvascular complications between those who achieved a HDL-C ≥ 1.02 mmol/l, and among those who achieved triglycerides ≤1.7 mmol/l., Conclusions: Optimal control of glycemia and blood pressure, but not lipids is associated with a lower prevalence of diabetic microvascular complications., Competing Interests: Declaration of competing interest The authors report no conflict of interest in relation to this manuscript., (Copyright © 2021 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

Objective: Impaired rate-dependent depression of the Hoffman reflex (HRDD) is a marker of spinal inhibitory dysfunction and has previously been associated with painful neuropathy in a proof-of-concept study in patients with type 1 diabetes. We have now undertaken an assessment of HRDD in patients with type 1 or type 2 diabetes., Research Design and Methods: A total of 148 participants, including 34 healthy control subjects, 42 patients with painful diabetic neuropathy, and 62 patients with diabetic neuropathy without pain, underwent an assessment of HRDD and a detailed assessment of peripheral neuropathy, including nerve conduction studies, corneal confocal microscopy, and thermal threshold testing., Results: Compared with healthy control subjects ( P < 0.001) and patients without pain ( P < 0.001), we found that HRDD is impaired in patients with type 1 or type 2 diabetes with neuropathic pain. These impairments are unrelated to diabetes type and the presence or severity of neuropathy. In contrast, patients without neuropathic pain ( P < 0.05) exhibited enhanced HRDD compared with control subjects., Conclusions: We suggest that loss or impairment of HRDD may help to identify a subpopulation of patients with painful diabetic neuropathy mediated by impaired spinal inhibitory systems who may respond optimally to therapies that target spinal or supraspinal mechanisms. Enhanced RDD in patients without pain may reflect engagement of spinal pain-suppressing mechanisms., (© 2021 by the American Diabetes Association.)

Purpose: Increased corneal and epidermal Langerhans cells (LCs) have been reported in patients with diabetic neuropathy. The aim of this study was to quantify the density of LCs in relation to corneal nerve morphology and the presence of diabetic neuropathy and to determine if this differed in patients with type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and latent autoimmune diabetes of adults (LADA)., Methods: Patients with T1DM (n = 25), T2DM (n = 36), or LADA (n = 23) and control subjects (n = 23) underwent detailed assessment of peripheral neuropathy and corneal confocal microscopy. Corneal nerve fiber density (CNFD), branch density (CNBD), length (CNFL) and total, immature and mature LC densities were quantified., Results: Lower CNFD (P < 0.001), CNBD (P < 0.0001), and CNFL (P < 0.0001) and higher LC density (P = 0.03) were detected in patients with T1DM, T2DM, and LADA compared to controls. CNBD was inversely correlated with mature (r = -0.5; P = 0.008), immature (r = -0.4; P = 0.02) and total (r = -0.5; P = 0.01) LC density, and CNFL was inversely correlated with immature LC density (r = -0.4; P = 0.03) in patients with T1DM but not in patients with T2DM and LADA., Conclusions: This study shows significant corneal nerve loss and an increase in LC density in patients with T1DM, T2DM, and LADA. Furthermore, increased LC density correlated with corneal nerve loss in patients with T1DM.

Background: Immune-mediated neuropathies, such as chronic inflammatory demyelinating polyneuropathy (CIDP) are treatable neuropathies. Among individuals with diabetic neuropathy, it remains a challenge to identify those individuals who develop CIDP. Corneal confocal microscopy (CCM) has been shown to detect corneal nerve fiber loss and cellular infiltrates in the sub-basal layer of the cornea. The objective of the study was to determine whether CCM can distinguish diabetic neuropathy from CIDP and whether CCM can detect CIDP in persons with coexisting diabetes., Methods: In this multicenter, case-control study, participants with CIDP (n = 55) with (n = 10) and without (n = 45) diabetes; participants with diabetes (n = 58) with (n = 28) and without (n = 30) diabetic neuropathy, and healthy controls (n = 58) underwent CCM. Corneal nerve fiber density (CNFD), corneal nerve fiber length (CNFL), corneal nerve branch density (CNBD), and dendritic and non-dendritic cell density, with or without nerve fiber contact were quantified., Results: Dendritic cell density in proximity to corneal nerve fibers was significantly higher in participants with CIDP with and without diabetes compared to participants with diabetic neuropathy and controls. CNFD, CNFL, and CNBD were equally reduced in participants with CIDP, diabetic neuropathy, and CIDP with diabetes., Conclusions: An increase in dendritic cell density identifies persons with CIDP. CCM may, therefore, be useful to differentiate inflammatory from non-inflammatory diabetic neuropathy.

Diabetic ketoacidosis (DKA) is an acute complication of diabetes mellitus that can be associated with increased morbidity and mortality, particularly if it is diagnosed late and not treated appropriately. The management of DKA includes careful clinical evaluation, correction of metabolic abnormalities with intravenous fluids, insulin and electrolyte replacement with frequent monitoring of the patients' clinical and laboratory findings and also identification and treatment of the precipitating condition. There are special populations where features, management and outcome may differ from the usual patient with diabetes. Data on management of DKA in such special populations such as chronic kidney disease and pregnancy are sparse and recommendations are based mainly on small case series and expert opinion. Clinicians need to recognize and manage euglycaemic DKA in patients prescribed sodium-glucose cotransporter inhibitors. DKA is particularly a major health concern due to high rates of hospital admissions and mortality in resource-limited settings due to financial constraints, limiting the adequate provision of insulin and access to health care systems, and dysfunctional health systems. We review the challenges of diagnosis and management of DKA in these specific groups and provide recommendations on optimal patient care., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Patients with schizophrenia are at least twice as likely to develop diabetes mellitus compared to the general population. This is of significance in Qatar given the high prevalence of obesity and diabetes. Furthermore, the lifespan of people with schizophrenia is shortened by approximately 15 years, partly due to long-term microvascular and macrovascular complications. High quality diabetes care can significantly reduce morbidity and mortality. We assessed the level of diabetes care delivered to patients in Qatar with schizophrenia and diabetes compared to those with diabetes alone., Methods: We performed a retrospective chart review of patients with diabetes mellitus with (n = 73) and without (n = 73) schizophrenia. Demographic information and electronic medical records were reviewed to determine adherence to American Diabetes Association standards of diabetes care in the last 6 and 12 months. Optimal diabetes care was defined as having completed glycated hemoglobin (HbA1c), lipid profile and retinal examination within 12 months., Results: Optimal diabetes care was significantly lower in patients with schizophrenia and diabetes compared to diabetes alone [26.0% (n = 19/73) vs 52.1% (n = 38/73), p = 0.002]. Patients with diabetes and schizophrenia were also significantly less likely to have had body mass index recorded within 6 months (p = 0.008) and HbA1c (p = 0.006), lipid profile (p = 0.015), estimated glomerular filtration rate (eGFR) (p = 0.001) and order for retinal examination (p = 0.004) over 12 months. After adjusting for multiple comparisons, only assessment of eGFR (p = 0.01) and order for retinal examination (p = 0.04) remained significant., Conclusion: Patients in Qatar with schizophrenia and diabetes, receive sub-optimal diabetes care compared to those with diabetes alone.

Background and Hypothesis: Patients with type-2 diabetes mellitus (T2DM) on multiple glucose-lowering therapies who fast during Ramadan are at increased risk of hypoglycemia. We have assessed the utility of the flash glucose monitoring system after adjusting the dose of insulin and sulphonylureas to mitigate the risk of hypoglycemia in patients with T2DM who fast during Ramadan., Patients and Methods: Patients with T2DM on either basal insulin or a sulphonylurea and at least 2 other glucose-lowering agents received structured education and adjustment of insulin or sulphonylurea dose according to the PROFAST Ramadan protocol. Glucose variability and episodes of hypoglycemia were assessed using the flash glucose monitoring system (Free Style Libre) before and during Ramadan., Results: A total of 33 patients with T2DM (on sulphonylurea (SU+) (n = 21), on basal insulin (BI+) (n = 12) aged 50.8 ± 1.6 years with a diabetes duration of 13.1 ± 6.5 years were studied. The average sensor glucose was 154 ± 34 mg/dl (8.5 ± 1.88 mmol/l) with 65.2% in the target range before Ramadan and the average sensor glucose was 156 ± 36 mg/dl (8.6 ± 2.0 mmol/l) with 67.1% in the target range during Ramadan. The incidence of hypoglycemia in the whole group (2.9 v 2.9) and in the SU+ (3.7 vs 3.0) and BI+ (1.7 vs 2.9) groups and eHbA1c (P = 0.56, P = 0.93), average glucose (P = 0.56, P = 0.92) and time within range (P = 0.63, P = 0.73) did not change in the SU+ and BI+ groups, respectively, before and during Ramadan., Conclusion: Structured education with adjustment of the dose of glucose lowering medication alongside use of the FGMS can effectively mitigate the increased risk of hypoglycemia in patients with T2DM on multiple glucose-lowering therapies who fast during Ramadan., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

Purpose: There are limited data on the impact of bariatric surgery on microvascular complications of type 2 diabetes (T2D), particularly diabetic neuropathy. We assessed microvascular complications (especially neuropathy) in obese patients with T2D before and 12 months after bariatric surgery., Materials and Methods: This was a prospective observational cohort study. Measurements of neuropathy symptom profile (NSP), neuropathy disability score (NDS), vibration (VPT), cold (CPT) and warm (WPT) perception thresholds, nerve conduction studies (NCS) and corneal confocal microscopy (CCM) to quantify corneal nerve fibre density (CNFD), branch density (CNBD) and fibre length (CNFL); urinary albumin/creatinine ratio (uACR), estimated glomerular filtration rate (eGFRcyst-creat) and retinal grading were taken., Results: Twenty-six (62% female; median age 52 years) obese patients with T2D were recruited. Body mass index (BMI) (47.2 to 34.5 kg/m 2 ; p < 0.001) decreased post-operatively. There were improvements in CNFD (27.1 to 29.2/mm 2 ; p = 0.005), CNBD (63.4 to 77.8/mm 2 ; p = 0.008), CNFL (20.0 to 20.2/mm 2 ; p = 0.001), NSP (3 to 0/38; p < 0.001) and eGFRcyst-creat (128 to 120 ml/min; p = 0.015) post-bariatric surgery. Changes in (Δ) triglycerides were independently associated with ΔCNFL (β = - 0.53; p = 0.024) and Δsystolic blood pressure (β = 0.62;p = 0.017), and %excess BMI loss (β = - 0.004; p = 0.018) were associated with ΔeGFRcyst-creat. There was no significant change in NDS, VPT, CPT, WPT, NCS, uACR or retinopathy status. Glomerular hyperfiltration resolved in 42% of the 12 patients with this condition pre-operatively., Conclusion: Bariatric surgery results in improvements in small nerve fibres and glomerular hyperfiltration in obese people with T2D, which were associated with weight loss, triglycerides and systolic blood pressure, but with no change in retinopathy or uACR at 12 months.

Aims: This systematic review and meta-analysis aims to evaluate the safety and efficacy of the newer glucose lowering treatments on glycemic control, weight, blood pressure and hypoglycemia in patients with T2DM during Ramadan., Methods: A literature search was done in PubMed, Embase, and the Cochrane Library. Quality assessment was done using the ROBINS-I and Cochrane tools for risk of bias and analyses were performed using RevMan version 5.3., Results: A total of 20 studies were included in the meta-analysis. Dipeptidyl peptidase-4 inhibitors (DPP-4i) led to a significant reduction in Hb A1c (%) (SMD -0.25) and a non-significant decrease in weight (kg) (SMD -1.06) during Ramadan. Glucagon-like peptide (GLP-1) agonist therapy was associated with a significant decrease in Hb A1c (%) (SMD -0.68) and a non-significant decrease in weight (kg) (SMD -2.57) and systolic blood pressure (SBP) (mmHg) (SMD -3.50) after Ramadan. Sodium-glucose co-transporter 2 inhibitor (SGLT-2i) therapy was associated with a significant decrease in Hb A1c (%) (SMD -0.51) and a non-significant decrease in weight (kg) (SMD -1.41), SBP (SMD -1.10) and diastolic blood pressure (DBP) (mmHg) (SMD -2.08) after Ramadan., Conclusions: This systematic review and meta-analysis shows clinical benefits with the newer glucose lowering medications in patients with T2DM who fast during Ramadan., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: To assess the diagnostic utility of corneal confocal microscopy (CCM) for diabetic peripheral neuropathy (DPN) and the risk factors for corneal nerve loss., Research Design and Methods: A total of 490 participants, including 72 healthy control subjects, 149 with type 1 diabetes, and 269 with type 2 diabetes, underwent detailed assessment of peripheral neuropathy and CCM in relation to risk factors., Results: Corneal nerve fiber density (CNFD) ( P < 0.0001 and P < 0.0001), corneal nerve fiber branch density (CNBD) ( P < 0.0001 and P < 0.0001), and corneal nerve fiber length (CNFL) ( P < 0.0001 and P = 0.02) were significantly lower in patients with type 1 and type 2 diabetes compared with control subjects. CNFD ( P < 0.0001), CNBD ( P < 0.0001), and CNFL ( P < 0.0001) were lower in type 1 diabetes compared with type 2 diabetes. Receiver operating characteristic curve analysis for the diagnosis of DPN demonstrated a good area under the curve for CNFD of 0.81, CNBD of 0.74, and CNFL of 0.73. Multivariable regression analysis showed a significant association among reduced CNFL with age (β = -0.27, P = 0.007), HbA 1c (β = -1.1; P = 0.01), and weight (β = -0.14; P = 0.03) in patients with type 2 diabetes and with duration of diabetes (β = -0.13; P = 0.02), LDL cholesterol (β = 1.8, P = 0.04), and triglycerides (β = -2.87; P = 0.009) in patients with type 1 diabetes., Conclusions: CCM identifies more severe corneal nerve loss in patients with type 1 diabetes compared with type 2 diabetes and shows good diagnostic accuracy for DPN. Furthermore, the risk factors for a reduction in corneal nerve fiber length differ between type 1 and type 2 diabetes., (© 2020 by the American Diabetes Association.)

Introduction: Diabetic neuropathy can be diagnosed and assessed using a number of techniques including corneal confocal microscopy (CCM)., Research Design and Methods: We have undertaken quantitative sensory testing, nerve conduction studies and CCM in 143 patients with type 1 and type 2 diabetes without neuropathy (n=51), mild neuropathy (n=47) and moderate to severe neuropathy (n=45) and age-matched controls (n=30)., Results: Vibration perception threshold (p<0.0001), warm perception threshold (WPT) (p<0.001), sural nerve conduction velocity (SNCV) (p<0.001), corneal nerve fiber density (CNFD) (p<0.0001), corneal nerve branch density (CNBD) (p<0.0001), corneal nerve fiber length (CNFL) (p=0.002), inferior whorl length (IWL) (p=0.0001) and average nerve fiber length (ANFL) (p=0.0001) showed a progressive abnormality with increasing severity of diabetic neuropathy. Receiver operating characteristic curve analysis for the diagnosis of diabetic neuropathy showed comparable performance in relation to the area under the curve (AUC) but differing sensitivities and specificities for vibration perception threshold (AUC 0.79, sensitivity 55%, specificity 90%), WPT (AUC 0.67, sensitivity 50%, specificity 76%), cold perception threshold (AUC 0.64, sensitivity 80%, specificity 47%), SNCV (AUC 0.70, sensitivity 76%, specificity 54%), CNFD (AUC 0.71, sensitivity 58%, specificity 83%), CNBD (AUC 0.70, sensitivity 69%, specificity 65%), CNFL (AUC 0.68, sensitivity 64%, specificity 67%), IWL (AUC 0.72, sensitivity 70%, specificity 65%) and ANFL (AUC 0.72, sensitivity 71%, specificity 66%)., Conclusion: This study shows that CCM identifies early and progressive corneal nerve loss at the inferior whorl and central cornea and has comparable utility with quantitative sensory testing and nerve conduction in the diagnosis of diabetic neuropathy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To develop a machine-based algorithm from clinical and demographic data, physical activity and glucose variability to predict hyperglycaemic and hypoglycaemic excursions in patients with type 2 diabetes on multiple glucose lowering therapies who fast during Ramadan., Patients and Methods: Thirteen patients (10 males and three females) with type 2 diabetes on 3 or more anti-diabetic medications were studied with a Fitbit-2 pedometer device and Freestyle Libre (Abbott Diagnostics) 2 weeks before and 2 weeks during Ramadan. Several machine learning techniques were trained to predict blood glucose levels in a regression framework utilising physical activity and contemporaneous blood glucose levels, comparing Ramadan to non-Ramadan days., Results: The median age of participants was 51 years (IQR 49-52); median BMI was 33.2 kg/m 2 (IQR 33.0-35.9) and median HbA1c was 7.3% (IQR 6.7-7.8). The optimal model using physical activity achieved an R 2 of 0.548 and a mean absolute error (MAE) of 30.30. The addition of electronic health record (ehr) information increased R 2 to 0.636 and reduced MAE to 26.89 and the time of the day feature further increased R 2 to 0.768 and reduced MAE to 20.55. Combining all the features together resulted in an optimal XGBoost model with an R 2 of 0.836 and MAE of 17.47. This model accurately estimated normal glucose levels in 2584/2715 (95.2%) readings and hyperglycaemic events in 852/1031 (82.6%) readings, but fewer hypoglycaemic events (48/172 (27.9%)). The optimal XGBoost model prioritized age, gender, BMI and HbA1c followed by glucose levels and physical activity. Interestingly, the blood glucose level prediction by our model was influenced by use of SGLT2i., Conclusion: XGBoost, a machine learning AI algorithm achieves high predictive performance for normal and hyperglycaemic excursions, but has limited predictive value for hypoglycaemia in patients on multiple therapies who fast during Ramadan., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Corneal nerve fiber length (CNFL) represents a biomarker for diabetic distal symmetric polyneuropathy (DSP). We aimed to determine the reference distribution of annual CNFL change, the prevalence of abnormal change in diabetes, and its associated clinical variables., Research Design and Methods: We examined 590 participants with diabetes (399 with type 1 diabetes [T1D] and 191 with type 2 diabetes [T2D]) and 204 control patients without diabetes with at least 1 year of follow-up and classified them according to rapid corneal nerve fiber loss (RCNFL) if CNFL change was below the 5th percentile of the control patients without diabetes., Results: Control patients without diabetes were 37.9 ± 19.8 years old, had median follow-up of three visits over 3.0 years, and mean annual change in CNFL was -0.1% (90% CI -5.9% to 5.0%). RCNFL was defined by values exceeding the 5th percentile of 6% loss. Participants with T1D were 39.9 ± 18.7 years old, had median follow-up of three visits over 4.4 years, and mean annual change in CNFL was -0.8% (90% CI -14.0% to 9.9%). Participants with T2D were 60.4 ± 8.2 years old, had median follow-up of three visits over 5.3 years, and mean annual change in CNFL was -0.2% (90% CI -14.1% to 14.3%). RCNFL prevalence was 17% overall and was similar by diabetes type (64 T1D [16.0%], 37 T2D [19.4%], P = 0.31). RNCFL was more common in those with baseline DSP (47% vs. 30% in those without baseline DSP, P = 0.001), which was associated with lower peroneal conduction velocity but not with baseline HbA 1c or its change over follow-up., Conclusions: An abnormally rapid loss of CNFL of 6% per year or more occurs in 17% of diabetes patients. RCNFL may identify patients at highest risk for the development and progression of DSP., (© 2020 by the American Diabetes Association.)

Introduction: To assess the effect of exenatide and pioglitazone or basal-bolus insulin on diabetic peripheral neuropathy (DPN) in patients with poorly controlled type 2 diabetes (T2D)., Research Design and Methods: This is a substudy of the Qatar Study, an open-label, randomized controlled trial. 38 subjects with poorly controlled T2D were studied at baseline and 1-year follow-up and 18 control subjects were assessed at baseline only. A combination of exenatide (2 mg/week) and pioglitazone (30 mg/day) or glargine with aspart insulin were randomly assigned to patients to achieve an HbA1c <53 mmol/mol (<7%). DPN was assessed with corneal confocal microscopy (CCM), DN4, vibration perception and sudomotor function., Results: Subjects with T2D had reduced corneal nerves, but other DPN measures were comparable with the control group. In the combination treatment arm (n=21), HbA1c decreased by 35.2 mmol/mol (3.8 %) (p<0.0001), body weight increased by 5.6 kg (p<0.0001), corneal nerve branch density increased (p<0.05), vibration perception worsened (p<0.05), and DN4 and sudomotor function showed no change. In the insulin treatment arm, HbA1c decreased by 28.7 mmol/mol (2.7 %) (p<0.0001), body weight increased by 4.6 kg (p<0.01), corneal nerve branch density and fiber length increased (p≤0.01), vibration perception improved (p<0.01), and DN4 and sudomotor function showed no change. There was no association between the change in CCM measures with change in HbA1c, weight or lipids., Conclusions: Treatment with exenatide and pioglitazone or basal-bolus insulin results in corneal nerve regeneration, but no change in neuropathic symptoms or sudomotor function over 1 year., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: The aim of this systematic review and meta-analysis was to assess the effect of Ramadan focused education on clinical and metabolic parameters in patients with type 2 diabetes who fast during Ramadan., Methods: Literature search was done in PubMed, Embase (Ovid), and the Cochrane Library. Quality assessment was done using the ROBINS-I and Cochrane tools for risk of bias and analyses were performed using RevMan version 5.1., Results: From 770 records, 430 full text studies were assessed. After exclusions, the final quantitative analysis included 16 studies. Pre-Ramadan education was associated with a significant reduction in Hb A1c (SMD -0.46, 95% CI -0.65 to -0.27P < 0.05) and LDL (SMD -0.09, 95% CI -0.13 to -0.04P < 0.05), an increase in TG (SMD 0.07, 95% CI -0.23 to 0.93P < 0.05) and weight (SMD 0.44, 95% CI 0.06 to 0.81P < 0.05) and no change in hypoglycemic events, BMI, TC, HDL or blood pressure (P > 0.05) during Ramadan., Conclusions: This systematic review and meta-analysis shows that Ramadan-focused diabetes education leads to a decrease in Hb A1c and LDL, but an increase in TG and weight during Ramadan. It also identifies a lack of head to head studies and limited observational studies with adequately assessed end-points., Competing Interests: Declaration of Competing Interest No potential conflicts of interest relevant to this article., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Diabetic peripheral neuropathy in people with type 2 diabetes is poorly managed because of its insidious onset, delayed diagnosis and more complex aetiology resulting from the contribution of not only hyperglycaemia, but also ageing, hyperlipidaemia, hypertension and obesity. Because there is no US Food and Drug Adminstration-approved disease-modifying therapy for diabetic peripheral neuropathy, the key to ameliorating it in type 2 diabetes has to be through earlier diagnosis and timely multi-factorial risk factor reduction. The management of painful diabetic peripheral neuropathy also requires a detailed appraisal of the choice of therapy, taking into account efficacy, patient wishes, comorbidities, side effect profile and potential for abuse., (© 2019 Diabetes UK.)

Aims: The aim of this study was to evaluate the contribution of small and large fibre neuropathy to erectile dysfunction (ED) in men with type 2 diabetes (T2D)., Methods: Measures of small and large fibre neuropathy were evaluated in 49 participants with T2D and 20 age-matched controls., Results: ED was present in 59% of participants with T2D. There was no difference in age, duration of diabetes, blood pressure, lipid profile, vibration perception threshold (V) (14.3 ± 7.8 vs 11.2 ± 6.6, P = .429), peroneal (41.4 ± 8.2 vs 44.8 ± 4.4, P = .10) and sural (45.4 ± 5.6 vs 47.1 ± 5.8) nerve conduction velocities (m/s), cold (25.1 ± 3.8 vs 26.2 ± 2.9, P = .815) and warm (43.2 ± 4.0 vs 41.0 ± 3.8) perception thresholds (°C), and deep breathing heart rate variability (18 ± 8 vs 18 ± 8) between participants with and without ED. However, intraepidermal nerve fibre density (no./mm 2 ) (4.6 ± 2.8 vs 13.7 ± 2.7, P < .001), corneal nerve fibre density (no./mm 2 ) (23.5 ± 6.8 vs 31.3 ± 8.2, P < .001), corneal nerve fibre branch density (no./mm 2 ) (55.4 ± 35.3 vs 97.7 ± 46.4, P = .004), corneal nerve fibre length (mm/mm 2 ) (17.6 ± 6.8 vs 27.3 ± 6.8, P < .001), and sural (7.7 ± 6.1 vs 14.6 ± 6.7, P = .003) and peroneal (2.5 ± 2.0 vs 4.7 ± 2.0, P = .003) nerve amplitudes were significantly lower in participants with ED compared with those without ED., Conclusion: ED affects almost 2/3 of men with T2D and is associated with small nerve fibre damage but preserved nerve conduction and cardiac autonomic function. Corneal confocal microscopy may serve as a useful non-invasive imaging method to identify small fibre damage in patients with T2D and ED., (© 2019 John Wiley & Sons Ltd.)

Diabetic peripheral neuropathy (DPN) is diagnosed too late, which contrasts with our approach for diabetic retinopathy and nephropathy, where incipient disease is detected early enabling timely treatment. The 10-g monofilament and a foot exam are the commonly used methods for screening diabetic neuropathy, but this primarily identifies moderate to severe diabetic neuropathy. Small fibres are damaged early and are associated with the development of painful diabetic neuropathy, foot ulceration, and Charcot foot. Tests of small fibre damage include thermal thresholds, microneurography, evoked potentials, sudomotor function, laser Doppler flare, skin biopsy, and corneal confocal microscopy. Measures of small fibre damage and repair may be key to the assessment of efficacy in clinical trials of disease modifying therapies for diabetic neuropathy., (© 2019 John Wiley & Sons, Ltd.)

We conducted a narrative review of the medical and surgical management of people with obesity and diabetes. Results of this review showed that a 5-10% loss in body weight can be achieved with a change in lifestyle, diet and behaviour and with approved pharmacological therapies in people with obesity and diabetes. New targeted therapies are now available for patients with previously untreatable genetic causes of obesity. Compared to medical treatment, metabolic and bariatric surgery is associated with significantly higher rates of remission from type 2 diabetes and lower rates of incident macrovascular and microvascular complications and mortality. The National Institute for Health and Care Excellence and the American Diabetes Association endorse metabolic and bariatric surgery in obese adults with type 2 diabetes and there may also be a role for this in obese individuals with type 1 diabetes. The paediatric committee of the American Society for Metabolic and Bariatric Surgery have recommended metabolic and bariatric surgery in obese adolescents with type 2 diabetes. Earlier and more aggressive treatment with metabolic and bariatric surgery in obese or overweight people with diabetes can improve morbidity and mortality., (© 2019 Diabetes UK.)

Aims/introduction: Painful diabetic peripheral neuropathy (PDPN) has a significant impact on the patient's quality of life. The prevalence of PDPN in the Middle East and North Africa region has been reported to be almost double that of populations in the UK. We sought to determine the prevalence of PDPN and its associated factors in type 2 diabetes mellitus patients attending secondary care in Qatar., Materials and Methods: This was a cross-sectional study of 1,095 participants with type 2 diabetes mellitus attending Qatar's two national diabetes centers. PDPN and impaired vibration perception on the pulp of the large toes were assessed using the Douleur Neuropathique en 4 questionnaire with a cut-off ≥4 and the neurothesiometer with a cut-off ≥15 V, respectively., Results: The prevalence of PDPN was 34.5% (95% confidence interval [CI] 31.7-37.3), but 80% of these patients had not previously been diagnosed or treated for this condition. Arabs had a higher prevalence of PDPN compared with South Asians (P < 0.05). PDPN was associated with impaired vibration perception adjusted odds ratio (AOR) 4.42 (95% CI 2.92-6.70), smoking AOR 2.43 (95% CI 1.43-4.15), obesity AOR 1.74 (95% CI 1.13-2.66), being female AOR 1.65 (95% CI: 1.03-2.64) and duration of diabetes AOR 1.08 (95% CI 1.05-1.11). Age, poor glycemic control, hypertension, physical activity and proteinuria showed no association with PDPN., Conclusions: PDPN occurs in one-third of type 2 diabetes mellitus patients attending secondary care in Qatar, but the majority have not been diagnosed. Arabs are at higher risk for PDPN. Impaired vibration perception, obesity and smoking are associated with PDPN in Qatar., (© 2019 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Objective: The 'PROspective Study of dose adjustment of multiple anti-diabetic therapy for Type-2 diabetic patients FASTing the Month of Ramadan aimed to assess the biophysical and metabolic effects of fasting during Ramadan, including HbA1c, weight, blood pressure and lipid profile., Study Design Methods: We performed a prospective study of people with Type-2 diabetes who were on ≥3 drugs for lowering glucose before and after Ramadan of H1438 (May-June 2017) in Hamad Medical Corporation, Qatar. We enrolled 228 participants, of whom 181 completed the study and were included in the analysis., Results: There were 115 (63.5%) men and 66 (36.5%) women, mean age 53.6 ± 9.7 years and mean diabetes duration of 10 ± 6 years. Both HBA1c [7.8% (62 mmol/mol) vs. 7.6% (60 mmol/mol); p = 0.004]; and diastolic BP (75.7 ± 8.55 vs. 68.8 ± 23.1 mmHg, P = 0.001) improved significantly after Ramadan while there was an increase in total cholesterol (3.94 ± 0.89 mmol/l vs 4.11 ± 1.02 mmol/l; p = 0.008) and triglycerides (1.55 ± 0.72 mmol/l vs 1.71 ± 0.9 mmol/l; p = 0.012). Subgroup analysis showed that patients on sulphonylurea, South Asians and males had a significant reduction in both HBA1c and weight., Conclusion: Patients with Type 2 diabetes who fast during Ramadan show an improvement in glycaemic control and diastolic blood pressure, but a worsening of total cholesterol and triglycerides, particularly those of South Asian origin and men., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Reaven originally described the clustering of insulin resistance/hyperinsulinaemia, obesity (particularly visceral), altered cytokine levels, glucose intolerance, hypertriglyceridaemia and low high-density lipoprotein cholesterol. Subsequently, a potentially highly atherogenic small, dense low-density lipoprotein was also reported. We have studied the effect of bariatric surgery on this and other risk factors for atherosclerosis., Methods: Forty patients (20 with type 2 diabetes mellitus) undergoing bariatric surgery were studied before and 1 year after bariatric surgery., Results: Twelve months after bariatric surgery, median body mass index had decreased from 49.5 to 36.5 kg/m 2 , fasting insulin from 21.3 to 7.8 mU/L and insulin resistance (homeostatic model assessment of insulin resistance) from 5.9 to 1.8 (all p < 0.001). Thirteen out of 20 patients had remission from type 2 diabetes mellitus. Highly sensitive C-reactive protein, interleukin-6, fasting triglycerides ( p < 0.001) and small, dense low-density lipoprotein ( p < 0.001) decreased, while high-density lipoprotein cholesterol increased ( p < 0.001) significantly, irrespective of having type 2 diabetes mellitus and/or being treated with statin therapy before surgery., Conclusion: The association between marked weight loss and change in insulin resistance and hyperinsulinaemia with the change in small, dense low-density lipoprotein and interleukin-6 warrants further investigation. Bariatric surgery provides a model for investigating the mechanisms linking insulin resistance/hyperinsulinaemia to atherosclerosis.