Fasting pancreatic polypeptide predicts incident microvascular and macrovascular complications of type 2 diabetes: An observational study.

AIMS: Pancreatic polypeptide (PP) is elevated in people with vascular risk factors such as type 2 diabetes or increased visceral fat. We investigated potential relationships between PP and microvascular and macrovascular complications of diabetes. MATERIALS AND METHODS: Animal study: Subcutaneous PP infusion for 4 weeks in high fat diet mouse model. Retinal mRNA submitted for Ingenuity Pathway Analysis. Human study: fasting PP measured in 1478 participants and vascular complications recorded over median 5.5 (IQR 4.9-5.8) years follow-up. RESULTS: Animal study: The retinal transcriptional response to PP was indicative of cellular stress and damage, and this footprint matched responses described in previously published studies of retinal disease. Of mechanistic importance the transcriptional landscape was consistent with upregulation of folliculin, a recently identified susceptibility gene for diabetic retinopathy. Human study: Adjusting for established risk factors, PP was associated with prevalent and incident clinically significant retinopathy (odds ratio (OR) 1.289 (1.107-1.501) p = 0.001; hazard ratio (HR) 1.259 (1.035-1.531) p = 0.0213), albuminuria (OR 1.277 (1.124-1.454), p = 0.0002; HR 1.608 (1.208-2.141) p = 0.0011), and macrovascular disease (OR 1.021 (1.006-1.037) p = 0.0068; HR 1.324 (1.089-1.61), p = 0.0049), in individuals with type 2 diabetes, and progression to diabetes in non-diabetic individuals (HR 1.402 (1.081-1.818), p = 0.0109). CONCLUSIONS: Elevated fasting PP is independently associated with vascular complications of diabetes and affects retinal pathways potentially influencing retinal neuronal survival. Our results suggest possible new roles for PP-fold peptides in the pathophysiology of diabetes complications and vascular risk stratification.

Real world use of tirzepatide in the treatment of type 2 diabetes in an Arab population.

AIM: Tirzepatide is a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) dual receptor agonist (RA) that reduces glycated haemoglobin (HbA1c) and weight in patients with type 2 diabetes. We assessed the effectiveness of tirzepatide in real-world use in an Arab population. METHODS: Review of clinical data from a specialist outpatient diabetes centre; study time points and outcome measures were pre-specified. RESULTS: Tirzepatide was initiated in 8945 patients between 24 October 2022 and 31 December 2023. Of these, 3686 individuals reached 40 weeks of follow-up. At initiation, the mean ± SD age was 54.1 ± 11.5 years, body mass index 34.6 ± 6.0 kg/m2 and HbA1c 7.3 ± 1.5% (56 ± 17 mmol/mol); 2296 (62%) were switched to tirzepatide from another GLP-RA and 317 (8.6%) reported previous bariatric surgery. The maximum dose dispensed was ≥12.5 mg/week in 1087, 7.5-10.0 mg/week in 1688 and 2.5-5.0 mg/week in 911. The mean 40-week reduction in HbA1c was 0.6 ± 1.2% (8 ± 13 mmol/mol) and the reduction in weight was 4.5 ± 6.9 kg (4.8 ± 7.3%). GLP-RA-naïve patients experienced a significantly greater reduction in HbA1c [1.0 ± 1.3% (11 ± 14 mmol/mol) versus 0.5 ± 1.2% (6 ± 13 mmol/mol), p < .0001] and weight (7.2 ± 8.6 vs. 4.2 ± 6.6 kg, p < .0001) compared with previously exposed individuals. Post-metabolic bariatric surgery patients lost significantly more weight (7.8 ± 9.4 vs. 4.5 ± 7.0 kg, p < .0001). Improvements in blood pressure, lipid profile, and liver transaminases were noted at 40 weeks. Tirzepatide was well tolerated, with 288 (7.8%) of patients discontinuing treatment because of adverse effects, predominantly gastrointestinal. CONCLUSION: In real-world use, tirzepatide significantly reduced HbA1c levels and weight and was well tolerated. Previous GLP-RA use was associated with significantly lesser HbA1c and weight reduction, and previous metabolic bariatric surgery was associated with greater weight loss.

Molecular and pro-inflammatory aspects of COVID-19: The impact on cardiometabolic health.

Obesity, type 2 diabetes (T2DM), hypertension (HTN), and Cardiovascular Disease (CVD) often cluster together as "Cardiometabolic Disease" (CMD). Just under 50% of patients with CMD increased the risk of morbidity and mortality right from the beginning of the COVID-19 pandemic as it has been reported in most countries affected by the SARS-CoV2 virus. One of the pathophysiological hallmarks of COVID-19 is the overactivation of the immune system with a prominent IL-6 response, resulting in severe and systemic damage involving also cytokines such as IL2, IL4, IL8, IL10, and interferon-gamma were considered strong predictors of COVID-19 severity. Thus, in this mini-review, we try to describe the inflammatory state, the alteration of the adipokine profile, and cytokine production in the obese state of infected and not infected patients by SARS-CoV2 with the final aim to find possible influences of COVID-19 on CMD and CVD. The immunological-based discussion of the molecular processes could inspire the study of promising targets for managing CMD patients and its complications during COVID-19.

Physical activity and fat-free mass during growth and in later life.

BACKGROUND: Physical activity may be a way to increase and maintain fat-free mass (FFM) in later life, similar to the prevention of fractures by increasing peak bone mass. OBJECTIVES: A study is presented of the association between FFM and physical activity in relation to age. METHODS: In a cross-sectional study, FFM was analyzed in relation to physical activity in a large participant group as compiled in the International Atomic Energy Agency Doubly Labeled Water database. The database included 2000 participants, age 3-96 y, with measurements of total energy expenditure (TEE) and resting energy expenditure (REE) to allow calculation of physical activity level (PAL = TEE/REE), and calculation of FFM from isotope dilution. RESULTS: PAL was a main determinant of body composition at all ages. Models with age, fat mass (FM), and PAL explained 76% and 85% of the variation in FFM in females and males < 18 y old, and 32% and 47% of the variation in FFM in females and males ≥ 18 y old, respectively. In participants < 18 y old, mean FM-adjusted FFM was 1.7 kg (95% CI: 0.1, 3.2 kg) and 3.4 kg (95% CI: 1.0, 5.6 kg) higher in a very active participant with PAL = 2.0 than in a sedentary participant with PAL = 1.5, for females and males, respectively. At age 18 y, height and FM-adjusted FFM was 3.6 kg (95% CI: 2.8, 4.4 kg) and 4.4 kg (95% CI: 3.2, 5.7 kg) higher, and at age 80 y 0.7 kg (95% CI: -0.2, 1.7 kg) and 1.0 kg (95% CI: -0.1, 2.1 kg) higher, in a participant with PAL = 2.0 than in a participant with PAL = 1.5, for females and males, respectively. CONCLUSIONS: If these associations are causal, they suggest physical activity is a major determinant of body composition as reflected in peak FFM, and that a physically active lifestyle can only partly protect against loss of FFM in aging adults.

Bariatric surgery in the treatment of patients with obesity and type 1 diabetes: A retrospective study of clinical data.

AIM: To evaluate the effectiveness and safety of bariatric surgery in patients with coexisting type 1 diabetes and obesity who choose to undergo bariatric surgery for weight management. MATERIALS AND METHODS: We conducted a retrospective, longitudinal review of the clinical data of patients with type 1 diabetes, followed up at our centre after bariatric surgery had been performed elsewhere. RESULTS: Sixty-one patients were included, of whom 51% were women, and 57 (93%) were Emirati Arab, three (5%) were other Arab, and one (2%) was White in ethnic origin. The mean age at surgery was 31 years. A total of 42 patients (69%) underwent sleeve gastrectomy, 17 (28%) gastric bypass, and two (3%) gastric banding. In 48 patients with complete follow-up data, improvements were observed at 12 months in the median (interquartile range [IQR]) values for body mass index (BMI; 38.5 [34.9-40.9] to 26.1 [24.2-29.6] kg/m2 , P <0.001), glycated haemoglobin concentration (8.6 [7.8-9.2]% to 7.8 [7.2-8.5]%; P <0.001), daily insulin dose (1.0 [0.7-1.2] to 0.8 [0.6-0.9] units/kg/d; P <0.001), systolic blood pressure (127 [116-136] to 116 [110-120] mmHg; P <0.001), total cholesterol: high-density lipoprotein cholesterol ratio (3.4 [2.9-4.3] to 3.0 [2.6-3.5]; P <0.001), and albuminuria. In 32 patients followed up at 3 years, the median (IQR) reduction in BMI was 10.4 (5.9-11.7) kg/m2 , 50% reduced or stopped antihypertensive medication and 58% reduced or stopped lipid-modifying medication. Three patients each reported a single episode of diabetic ketoacidosis; in one case this was due to cessation of insulin treatment. CONCLUSIONS: In our cohort of patients with obesity and type 1 diabetes, bariatric surgery led to significant improvements in weight and cardiometabolic variables, with modest improvements in glycaemia. Few adverse events were reported.

Weight and Glycemic Control Outcomes of Bariatric Surgery and Pharmacotherapy in Patients With Melanocortin-4 Receptor Deficiency.

Background: Melanocortin-4 receptor (MC4R) mutations are the most common of the rare monogenic forms of obesity. However, the efficacy of bariatric surgery (BS) and pharmacotherapy on weight and glycemic control in individuals with MC4R deficiency (MC4R-d) is not well-established. We investigated and compared the outcomes of BS and pharmacotherapy in patients with and without MC4R-d. Methods: Pertinent details were derived from the electronic database among identified patients who had BS with MC4R-d (study group, SG) and wild-type controls (age- and sex-matched control group, CG). Short- and long-term outcomes were reported for the SG. Short-term outcomes were compared between the two groups. Results: Seventy patients were screened for MC4R-d. The SG [six individuals (four females, two males); 18 (10-27) years old at BS; 50.3 (41.8-61.9) kg/m2 at BS, three patients with homozygous T162I mutations, two patients with heterozygous T162I mutations, and one patient with heterozygous I170V mutation] had a follow-up duration of up to 10 years. Weight loss, which varied depending on mutation type [17.99 (6.10-22.54) %] was stable for 6 months; heterogeneity of results was observed thereafter. BS was found superior to liraglutide on weight and glycemic control outcomes. At a median follow-up of 6 months, no significant difference was observed on weight loss (20.8% vs. 23.0%, p = 0.65) between the SG and the CG [eight individuals (four females, four males); 19.0 (17.8-36.8) years old at BS, 46.2 (42.0-48.3) kg/m2 at BS or phamacotherapeutic intervention]. Glycemic control in patients with MC4R-d and Type 2 diabetes improved post-BS. Conclusion: Our data indicate efficacious short-term but varied long-term weight loss and glycemic control outcomes of BS on patients with MC4R-d, suggesting the importance of ongoing monitoring and complementary therapeutic interventions.

Obesity and Diabetes in an Arab population: Role of Adenovirus 36 Infection.

Prior infection with adenovirus 36 (Adv36) has been associated with increased adiposity, improved insulin sensitivity, and a lower prevalence of diabetes. This study investigated the prevalence of Adv36 seropositivity and its association with obesity and diabetes among adults attending a diabetes centre in the UAE.Participants (N = 973) with different weight and glucose tolerance categories were recruited. Adv36 seropositivity (Adv36 + ) was assessed using ELISA. Differences among groups were analyzed using statistical tests as appropriate to the data. Prevalence of Adv36+ in the study population was 47%, with no significant difference in obese and non-obese subgroups (42.5% vs 49.6% respectively; p=non-significant). Females were more likely to be Adv36+ compared to males (odds ratio 1.78; 95% CI 1.36-2.32, p < 0.001). We found no significant association between Adv36 seropositivity and different BMI categories, or glucose tolerance status. In our population, the effect of Adv36 infection on lipid profile varied between healthy individuals and individuals with obesity. Adv36 infection is more prevalent in the UAE than in other countries but has no association with obesity. Our study found that females were more likely to be Adv36 positive regardless of weight or diabetes status.

Routine clinical use of liraglutide 3 mg for the treatment of obesity: Outcomes in non-surgical and bariatric surgery patients.

In this study we prospectively collected data on the use of liraglutide 3 mg in obese Arab patients. As part of routine care, 2092 patients were dispensed liraglutide 3 mg. Median age was 38 years and 77% were women. Median baseline weight was 95 kg and body mass index was 36.6 kg/m2 . Of the patients, 188 (9%) had previous bariatric surgery. Seven hundred and eighty-seven patients were treated for ≥16 weeks and their median (interquartile range) weight loss was 6.0 (2.4-9.4) kg, equivalent to 6.4% (2.6%-9.7%) of baseline weight (P < 0.0001, n = 787). Of those treated for ≥16 weeks, 474 (60%) achieved a weight loss of >5% of baseline weight while 182 (23%) achieved >10% weight loss. There was no difference in percentage weight loss between postbariatric surgery (n = 76) and non-surgical patients (n = 711). As a result of adverse events, mainly gastrointestinal symptoms, 140 (6.7%) of the patients stopped treatment. One patient developed acute pancreatitis in the context of gallstone disease but made an uneventful recovery. Liraglutide 3 mg was well tolerated and resulted in weight loss in routine clinical care similar to that seen in randomized controlled trials.

Non-alcoholic fatty liver disease: Relationship with cardiovascular risk markers and clinical endpoints.

Non-alcoholic fatty liver disease (NAFLD) is a common diagnosis and is increasing in prevalence worldwide. NAFLD is usually asymptomatic at presentation; progression of the disease is unpredictable, leading to the development of a variety of techniques for screening, diagnosis and risk stratification. Clinical methods in current use include serum biomarker panels, hepatic ultrasound, magnetic resonance imaging, and liver biopsy. NAFLD is strongly associated with the metabolic syndrome, and the most common cause of death for people with the condition is cardiovascular disease. Whether NAFLD is an independent cardiovascular risk factor needs exploration. NAFLD has been associated with surrogate markers of cardiovascular disease such as carotid intima-media thickness, the presence of carotid plaque, brachial artery vasodilatory responsiveness and CT coronary artery calcification score. There is no effective medical treatment for NAFLD and evidence is lacking regarding the efficacy of interventions in mitigating cardiovascular risk. Health care professionals managing patients with NAFLD should tackle the issue with early identification of risk factors and aggressive modification. Current management strategies therefore comprise lifestyle change, with close attention to known cardiovascular risk factors.

Indeterminate Thyroid Nodules: A Pragmatic Approach.

BACKGROUND: Fine needle aspiration (FNA) cytology fails to provide a conclusive diagnosis in a subset of thyroid lesions labeled as "indeterminate" (Thy3). In this study, we aimed at ascertaining the prevalence of Thy3 thyroid nodules in a hitherto unreported ethnic group (residents of the United Arab Emirates). METHODS: We retrospectively examined 688 FNA of the thyroid performed on 584 patients. Samples were reported using the Royal College of Physicians' (RCP) Thy classification. The results of the FNA were correlated with the final surgical specimens. Ultrasonography (US) risk stratification was calculated using a web-based US risk of malignancy calculator. RESULTS: Overall sample adequacy was 97%. The indeterminate group Thy3 was found in 7% of the samples. The overall risk of malignancy in the Thy3 category was 20%. This risk was very similar in the 2 subgroups of Thy3 (17% in Thy 3a and 22% in Thy3f). Subdividing the Thy3 group into subgroups becomes less necessary if the US scoring is <24.5% since the negative predictive value, in this case, is 100%. Applying this criterion to our population would have had the potential of reducing the percentage of patients referred to surgery from 61 to 43%. CONCLUSIONS: Proper risk stratification of Thy3 lesions should be based on the combined risk assessment of clinical, cytological, radiological, and molecular data. Such a pragmatic approach is expected to reduce the percentage of inappropriate referrals to surgery.

Subclinical Inflammation and Endothelial Dysfunction in Young Patients with Diabetes: A Study from United Arab Emirates.

BACKGROUND: The impact of obesity and dyslipidemia on cardiovascular health in adolescents and young adults with diabetes is incompletely understood. This study evaluated the effects of these co-morbidities on markers of inflammation and endothelial dysfunction in young patients with the disease. METHODS: The study investigated sets of inflammatory, endothelial, and adipocyte biomarkers in 79 patients with type 1 diabetes, 55 patients with type 2 diabetes, and 47 controls. RESULTS: Mean (±SD) age was 20±6 y (median = 17, range = 12-31). Patients with diabetes had higher levels of cytoadhesive molecules (sICAM-1 and sVCAM-1, p<0.001), adiponectin (p<0.001), and haptoglobin (p = 0.023). Their heart rate variability assessment revealed lower standard deviation of beat-to-beat intervals and lower total power (p≤0.019), reflecting autonomous nervous dysfunction. Hemoglobin A1c >8.0% (estimated average blood glucose >10 mmol/L) was associated with higher adiponectin (p<0.001) and obesity was associated with lower adiponectin (p<0.001); thus, obesity damped the effect of hyperglycemia on adiponectin. Obesity was associated with higher sICAM-1 (p≤0.015), tumor necrosis factor-α (TNFα), interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hs-CRP), p<0.001. Similarly, high-density lipoprotein (HDL) <1.02 mmol/L was associated with higher sICAM-1, TNFα, IL-6, and hsCRP (p≤0.009) and lower adiponectin (p<0.001). Adiponectin correlated negatively with the inflammatory biomarkers in patients with diabetes. CONCLUSION: Subclinical inflammation and endothelial dysfunction are common among young patients with diabetes. Poor diabetes control is associated with higher adiponectin. Obesity and dyslipidemia are associated with lower adiponectin and higher inflammatory and endothelial biomarkers. Intuitively, these predictors of cardiovascular disease are amenable to proper glycemic control, nutritional choices, and regular exercise.

Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor.

BACKGROUND: A single family has been described in which obesity results from a mutation in the leptin-receptor gene (LEPR), but the prevalence of such mutations in severe, early-onset obesity has not been systematically examined. METHODS: We sequenced LEPR in 300 subjects with hyperphagia and severe early-onset obesity, including 90 probands from consanguineous families, and investigated the extent to which mutations cosegregated with obesity and affected receptor function. We evaluated metabolic, endocrine, and immune function in probands and affected relatives. RESULTS: Of the 300 subjects, 8 (3%) had nonsense or missense LEPR mutations--7 were homozygotes, and 1 was a compound heterozygote. All missense mutations resulted in impaired receptor signaling. Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism. Serum leptin levels were within the range predicted by the elevated fat mass in these subjects. Their clinical features were less severe than those of subjects with congenital leptin deficiency. CONCLUSIONS: The prevalence of pathogenic LEPR mutations in a cohort of subjects with severe, early-onset obesity was 3%. Circulating levels of leptin were not disproportionately elevated, suggesting that serum leptin cannot be used as a marker for leptin-receptor deficiency. Congenital leptin-receptor deficiency should be considered in the differential diagnosis in any child with hyperphagia and severe obesity in the absence of developmental delay or dysmorphism.