International Diabetes Federation Position Statement on the 1-hour post-load plasma glucose for the diagnosis of intermediate hyperglycaemia and type 2 diabetes.

Many individuals with intermediate hyperglycaemia (IH), including impaired fasting glycaemia (IFG) and impaired glucose tolerance (IGT), as presently defined, will progress to type 2 diabetes (T2D). There is confirmatory evidence that T2D can be prevented by lifestyle modification and/or medications, in people with IGT diagnosed by 2-h plasma glucose (PG) during a 75-gram oral glucose tolerance test (OGTT). Over the last 40 years, a wealth of epidemiological data has confirmed the superior value of 1-h plasma glucose (PG) over fasting PG (FPG), glycated haemoglobin (HbA1c) and 2-h PG in populations of different ethnicity, sex and age in predicting diabetes and associated complications including death. Given the relentlessly rising prevalence of diabetes, a more sensitive, practical method is needed to detect people with IH and T2D for early prevention or treatment in the often lengthy trajectory to T2D and its complications. The International Diabetes Federation (IDF) Position Statement reviews findings that the 1-h post-load PG ≥ 155 mg/dL (8.6 mmol/L) in people with normal glucose tolerance (NGT) during an OGTT is highly predictive for detecting progression to T2D, micro- and macrovascular complications, obstructive sleep apnoea, cystic fibrosis-related diabetes mellitus, metabolic dysfunction-associated steatotic liver disease, and mortality in individuals with risk factors. The 1-h PG of 209 mg/dL (11.6 mmol/L) is also diagnostic of T2D. Importantly, the 1-h PG cut points for diagnosing IH and T2D can be detected earlier than the recommended 2-h PG thresholds. Taken together, the 1-h PG provides an opportunity to avoid misclassification of glycaemic status if FPG or HbA1c alone are used. The 1-h PG also allows early detection of high-risk people for intervention to prevent progression to T2D which will benefit the sizeable and growing population of individuals at increased risk of T2D. Using a 1-h OGTT, subsequent to screening with a non-laboratory diabetes risk tool, and intervening early will favourably impact the global diabetes epidemic. Health services should consider developing a policy for screening for IH based on local human and technical resources. People with a 1-h PG ≥ 155 mg/dL (8.6 mmol/L) are considered to have IH and should be prescribed lifestyle intervention and referred to a diabetes prevention program. People with a 1-h PG ≥ 209 mg/dL (11.6 mmol/L) are considered to have T2D and should have a repeat test to confirm the diagnosis of T2D and then referred for further evaluation and treatment. The substantive data presented in the Position Statement provides strong evidence for redefining current diagnostic criteria for IH and T2D by adding the 1-h PG.

Safety Assessment of Glucose-Lowering Drugs and Importance of Structured Education during Ramadan: A Systematic Review and Meta-Analysis.

BACKGROUND: Ramadan is the sacred month of the Islamic Hijri (lunar) calendar, and during this entire month, healthy adult Muslims abstain from eating and drinking from dawn to sunset. Muslims with Type 2 Diabetes Mellitus (T2DM) who choose to fast during Ramadan encounter major risks such as hypoglycemia, hyperglycemia, diabetic ketoacidosis, dehydration, and thrombosis. Although patients with poor glycemic control and on multiple insulin injections are at high risk and exempt from fasting, many still insist on it. Thus, healthcare professionals play a pivotal role in managing diabetes-related complications in patients who fast during Ramadan. However, there is a lack of standard guidelines to be followed in association with structured education and administration of drugs and dosage. Therefore, we performed a systematic review and meta-analysis of the literature to determine the safety and efficacy of different classes of drugs and the importance of structured education during Ramadan. METHODS: In this review, an extensive PubMed search was performed to obtain literature on T2DM patients who fast during the month of Ramadan until the year 2020. Preference was given to fully downloadable articles. The articles were extracted based on the eligibility criteria. The extracted data were analyzed using Review Manager software version 5.3. RESULTS: A total of 32 articles were included for the review and 7 studies for meta-analysis. Majority of the studies demonstrated the importance of structured education either as a group session or as a one-on-one session with the healthcare professionals in preventing diabetes-related risks during Ramadan. As far as glucose-lowering drugs are concerned, DPP-4 inhibitor combined with metformin remains the drug of choice for T2DM patients who fast during Ramadan. The newer class of glucose-lowering agents appear to lower the risk of hypoglycemia in comparison with sulphonylureas, while among sulphonylureas gliclazide is relatively safe. The meta-analysis indicates that DPP-4 inhibitors would significantly reduce the risk of hypoglycemia as compared to sulphonylurea (odds ratio = 0.38, 95% CI: 0.26 to 0.55, p < 0.00001). CONCLUSION: The results of our systematic review show that structured education and counselling by healthcare professionals can be an effective tool in preventing complications associated with fasting during Ramadan in people with T2DM. Additionally, the safest class of oral glucose-lowering drugs preferred during Ramadan fasting in T2DM patients is DPP-4 inhibitors.

Enhanced Adipose Expression of Interferon Regulatory Factor (IRF)-5 Associates with the Signatures of Metabolic Inflammation in Diabetic Obese Patients.

: Interferon regulatory factors (IRFs) are emerging as the metabolic transcriptional regulators in obesity/type-2 diabetes (T2D). IRF5 is implicated with macrophage polarization toward the inflammatory M1-phenotype, nonetheless, changes in the adipose expression of IRF5 in T2D and relationship of these changes with other markers of adipose inflammation remain unclear. Therefore, we determined the IRF5 gene expression in subcutaneous adipose tissue samples from 46 T2D patients including 35 obese (Body Mass Index/BMI 33.83 ± 0.42kg/m2) and 11 lean/overweight individuals (BMI 27.55 ± 0.46kg/m2) using real-time qRT-PCR. IRF5 protein expression was assessed using immunohistochemistry and confocal microscopy. Fasting plasma glucose, insulin, HbA1c, C-reactive protein, cholesterol, low- and high-density lipoproteins (LDL/HDL), and triglycerides were measured using commercial kits. IRF5 gene expression was compared with that of signature inflammatory markers and several clinico-metabolic indicators. The data (mean ± SEM) show the enhanced adipose IRF5 gene (p = 0.03) and protein (p = 0.05) expression in obese compared to lean/overweight diabetic patients. Adipose IRF5 transcripts in diabetic obese individuals associated positively with those of TNF-α, IL-18, IL-23A, CXCL8, CCL2, CCL7, CCR1/5, CD11c, CD68, CD86, TLR4/7/10, Dectin-1, FGL-2, MyD88, NF-κB, IRF3, and AML1 (p < 0.05). In diabetic lean/overweight subjects, IRF5 expression associated with BMI, body fat %age, glucose, insulin, homeostatic model assessment of insulin resistance (HOMA-IR, C-reactive protein (CRP), IL-5, and IL-1RL1 expression; while in all T2D patients, IRF5 expression correlated with that of IRF4, TLR2/8, and CD163. In conclusion, upregulated adipose tissue IRF5 expression in diabetic obese patients concurs with the inflammatory signatures and it may represent a potential marker for metabolic inflammation in obesity/T2D.

Genome-wide association study identifies novel risk variants from RPS6KA1, CADPS, VARS, and DHX58 for fasting plasma glucose in Arab population.

Consanguineous populations of the Arabian Peninsula, which has seen an uncontrolled rise in type 2 diabetes incidence, are underrepresented in global studies on diabetes genetics. We performed a genome-wide association study on the quantitative trait of fasting plasma glucose (FPG) in unrelated Arab individuals from Kuwait (discovery-cohort:n = 1,353; replication-cohort:n = 1,196). Genome-wide genotyping in discovery phase was performed for 632,375 markers from Illumina HumanOmniExpress Beadchip; and top-associating markers were replicated using candidate genotyping. Genetic models based on additive and recessive transmission modes were used in statistical tests for associations in discovery phase, replication phase, and meta-analysis that combines data from both the phases. A genome-wide significant association with high FPG was found at rs1002487 (RPS6KA1) (p-discovery = 1.64E-08, p-replication = 3.71E-04, p-combined = 5.72E-11; ß-discovery = 8.315; ß-replication = 3.442; ß-combined = 6.551). Further, three suggestive associations (p-values < 8.2E-06) with high FPG were observed at rs487321 (CADPS), rs707927 (VARS and 2Kb upstream of VWA7), and rs12600570 (DHX58); the first two markers reached genome-wide significance in the combined analysis (p-combined = 1.83E-12 and 3.07E-09, respectively). Significant interactions of diabetes traits (serum triglycerides, FPG, and glycated hemoglobin) with homeostatic model assessment of insulin resistance were identified for genotypes heterozygous or homozygous for the risk allele. Literature reports support the involvement of these gene loci in type 2 diabetes etiology.

Circulating angiopoietin-like protein 8 (betatrophin) association with HsCRP and metabolic syndrome.

BACKGROUND: ANGPTL8 also called betatrophin is a regulator of lipid metabolism through its interaction with ANGPTL3. It has also been suggested to play a role in insulin resistance and beta-cell proliferation. Based on its function, we hypothesized that ANGPTL8 will play a role in Metabolic Syndrome (MetS). To test this hypothesis we designed this study to measure ANGPTL8 level in subjects with MetS as well as its association with high sensitivity C-reactive protein (HsCRP) level in humans. METHODS: ANGPTL8 level was measured using ELISA in subjects with MetS as well as their controls, a total of 1735 subjects were enrolled. HsCRP was also measured and its association with ANGPTL8 was examined. RESULTS: ANGPTL8 level was higher in subjects with MetS 1140.6 (171.9-11736.1) pg/mL compared to 710.5 (59.5-11597.2) pg/mL in the controls. Higher levels of ANGPTL8 were also observed with the sequential increase in the number of MetS components (p value = <0.0001). ANGPTL8 showed strong positive correlation with HsCRP (r = 0.15, p value = <0.0001). Stratifying the population into tertiles according to the level of HsCRP showed increased ANGPTL8 level at higher tertiles of HsCRP in the overall population (p value = <0.0001).A similar trend was also observed in MetS and non-MetS subjects as well as in non-obese and obese subjects. Finally, multiple logistic regression models adjusted for age, gender, ethnicity and HsCRP level showed that subjects in the highest tertiles of ANGPTL8 had higher odds of having MetS (odd ratio [OR] = 2.3, 95 % confidence interval [CI] = (1.6-3.1), p value <0.0001. CONCLUSION: In this study we showed that ANGPTL8 is increased in subjects with MetS and it was significantly associated with HsCRP levels in different subgroups highlighting its potential role in metabolic and inflammatory pathways.

Lack of associations between betatrophin/ANGPTL8 level and C-peptide in type 2 diabetic subjects.

BACKGROUND: Betatrophin has been suggested as an inducer of ß-cell proliferation in mice in addition to its function in regulating triglyceride. Recent data showed that betatrophin was increased in Type 2 Diabetes (T2D), however, its ability to induce insulin production has been questioned. We hypothesized that the increased betatrophin in T2D is not affecting insulin production from ß-cells. To test this hypothesis, we investigated the association between betatrophin and C-peptide level in humans, which acts as a measure of endogenous insulin production from ß-cells. METHODS: This study was designed to examine the association between plasma betatrophin level and C-peptide in 749 T2D and non-diabetics. RESULTS: Betatrophin and C-peptide levels were higher in T2D subjects compared with non-diabetics subjects. Betatrophin showed strong correlation with C-peptide in non-diabetics subjects (r = 0.28, p = < 0.0001). No association between betatrophin and C-peptide were observed in T2D subjects (r = 0.07, p = 0.3366). Dividing obese and non-obese subjects into tertiles according to betatrophin level showed significantly higher C-peptide levels at higher tertiles of betatrophin in obese non-diabetics subjects P-trend = 0.0046. On the other hand, C-peptide level was significantly higher in subject with higher betatrophin level in non-diabetics subjects across all age groups but not in T2D subjects. Multiple logistic regression models adjusted for age, BMI, gender, ethnicity as well as C-peptide level showed that subjects in the highest tertiles of betatrophin had higher odds of having T2D [odd ratio (OR) = 7.3, 95% confidence interval (CI) 4.0-13.3]. CONCLUSION: Increased betatrophin level in obese subjects is correlated with an increase in C-peptide level; which is possibly caused by the increased insulin resistance. On the other hand, no correlation is observed between increased betatrophin level and C-peptide in T2D subjects. In conclusion, the increased betatrophin in T2D subject does not cause any increase in insulin production as indicated by C-peptide level.

Vitamin D insufficiency in Arabs and South Asians positively associates with polymorphisms in GC and CYP2R1 genes.

BACKGROUND: A number of genetic studies have reported an association between vitamin D related genes such as group-specific component gene (GC), Cytochrome P450, family 2, subfamily R, polypeptide 1 (CYP2R1) and 7-dehydrocholesterol reductase/nicotinamide-adenine dinucleotide synthetase 1 (DHCR7/NADSYN1) and serum levels of the active form of Vitamin D, 25 (OH) D among African Americans, Caucasians, and Chinese. Little is known about how genetic variations associate with, or contribute to, 25(OH)D levels in Arabs populations. METHODS: Allele frequencies of 18 SNPs derived from CYP2R1, GC, and DHCR7/NADSYN1 genes in 1549 individuals (Arabs, South Asians, and Southeast Asians living in Kuwait) were determined using real time genotyping assays. Serum levels of 25(OH)D were measured using chemiluminescence immunoassay. RESULTS: GC gene polymorphisms (rs17467825, rs3755967, rs2282679, rs7041 and rs2298850) were found to be associated with 25(OH)D serum levels in Arabs and South Asians. Two of the CYP2R1 SNPs (rs10500804 and rs12794714) and one of GC SNPs (rs1155563) were found to be significantly associated with 25(OH)D serum levels only in people of Arab origin. Across all three ethnicities none of the SNPs of DHCR7/NADSYN1 were associated with serum 25(OH)D levels and none of the 18 SNPs were significantly associated with serum 25(OH)D levels in people from South East Asia. CONCLUSION: Our data show for the first time significant association between the GC (rs2282679 and rs7041), CYP2R1 (rs10741657) SNPs and 25(OH)D levels. This supports their roles in vitamin D Insufficiency in Arab and South Asian populations respectively. Interestingly, two of the CYP2R1 SNPs (rs10500804 and rs12794714) and one GC SNP (rs1155563) were found to correlate with vitamin D in Arab population exclusively signifying their importance in this population.