XI. STRATEGIES FOR IMPROVING DIABETES CARE D iabetes is a chronic illness that requires continuing medical care and patient self-management education to prevent acute complications and to reduce the risk of long-term complications. Diabetes care is complex and requires that many issues, beyond glycemic control, be addressed. A large body of evidence exists that supports a range of interventions to improve diabetes outcomes. These standards of care are intended to provide clinicians, patients, researchers, payors, and other interested individuals with the components of diabetes care, treatment goals, and tools to evaluate the quality of care. While individual preferences, comorbidities, and other patient factors may require modification of goals, targets that are desirable for most patients with diabetes are provided. These standards are not intended to preclude more extensive evaluation and management of the patient by other specialists as needed. For more detailed information, refer to Bode (Ed.): Medical Management of Type 1 Diabetes (1), Burant (Ed): Medical Management of Type 2 Diabetes (2), and Klingensmith (Ed): Intensive Diabetes Management (3). The recommendations included are diagnostic and therapeutic actions that are known or believed to favorably affect health outcomes of patients with diabetes. A grading system (Table 1), developed by the American Diabetes Association (ADA) and modeled after existing methods, was utilized to clarify and codify the evidence that forms the basis for the recommendations. The level of evidence that supports each recommendation is listed after each recommendation using the letters A, B, C, or E.

Standards of Medical Care in Diabetes

1. Type 1 diabetes (due to b-cell destruction, usually leading to absolute insulin deficiency) 2. Type 2 diabetes (due to a progressive insulin secretory defect on the background of insulin resistance) 3. Gestational diabetes mellitus (GDM) (diabetes diagnosed in the second or third trimester of pregnancy that is not clearly overt diabetes) 4. Specific types of diabetes due to other causes, e.g., monogenic diabetes syndromes (such as neonatal diabetes and maturity-onset diabetes of the young [MODY]), diseases of the exocrine pancreas (such as cystic fibrosis), and drugor chemical-induced diabetes (such as in the treatment of HIV/AIDS or after organ transplantation)

Classification and diagnosis of diabetes

Single-nucleotide polymorphisms within intron 1 of the FTO (fat mass and obesity-associated) gene are associated with enhanced FTO expression, increased body weight, obesity and type 2 diabetes mellitus (T2DM). The N (6) -methyladenosine (m(6)A) demethylase FTO plays a pivotal regulatory role for postnatal growth and energy expenditure. The purpose of this review is to provide translational evidence that links milk signaling with FTO-activated transcription of the milk recipient. FTO-dependent demethylation of m(6)A regulates mRNA splicing required for adipogenesis, increases the stability of mRNAs, and affects microRNA (miRNA) expression and miRNA biosynthesis. FTO senses branched-chain amino acids (BCAAs) and activates the nutrient sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1), which plays a key role in translation. Milk provides abundant BCAAs and glutamine, critical components increasing FTO expression. CpG hypomethylation in the first intron of FTO has recently been associated with T2DM. CpG methylation is generally associated with gene silencing. In contrast, CpG demethylation generally increases transcription. DNA de novo methylation of CpG sites is facilitated by DNA methyltransferases (DNMT) 3A and 3B, whereas DNA maintenance methylation is controlled by DNMT1. MiRNA-29s target all DNMTs and thus reduce DNA CpG methylation. Cow´s milk provides substantial amounts of exosomal miRNA-29s that reach the systemic circulation and target mRNAs of the milk recipient. Via DNMT suppression, milk exosomal miRNA-29s may reduce the magnitude of FTO methylation, thereby epigenetically increasing FTO expression in the milk consumer. High lactation performance with increased milk yield has recently been associated with excessive miRNA-29 expression of dairy cow mammary epithelial cells (DCMECs). Notably, the galactopoietic hormone prolactin upregulates the transcription factor STAT3, which induces miRNA-29 expression. In a retrovirus-like manner milk exosomes may transfer DCMEC-derived miRNA-29s and bovine FTO mRNA to the milk consumer amplifying FTO expression. There is compelling evidence that obesity, T2DM, prostate and breast cancer, and neurodegenerative diseases are all associated with increased FTO expression. Maximization of lactation performance by veterinary medicine with enhanced miRNA-29s and FTO expression associated with increased exosomal miRNA-29 and FTO mRNA transfer to the milk consumer may represent key epigenetic mechanisms promoting FTO/mTORC1-mediated diseases of civilization.

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Milk: an epigenetic amplifier of FTO-mediated transcription? Implications for Western diseases.

In the 21st century, obesity has become a serious problem because of increasing obese patients and numerous metabolic complications. The primary reasons for this situation are environmental and genetic factors. In 2007, FTO (fat mass and obesity associated) was the first gene identified through a genome-wide association study (GWAS) associated with obesity in humans. Subsequently, a cluster of single nucleotide polymorphisms (SNPs) in the first intron of the FTO gene was discovered to be associated with BMI and body composition. Various studies have explored the mechanistic basis behind this association. Thus, emerging evidence showed that FTO plays a key role regulating adipose tissue development and functions in body size and composition. Recent prevalent research topic concentrated in the three neighboring genes of FTO: RPGRIP1L, IRX3 and IRX5, as having a functional link between obesity-associated common variants within FTO and the observed human phenotypes. The purpose of this review is to present a comprehensive picture of the impact of FTO on obesity susceptibility and to illuminate these new studies of FTO function in adipose tissue.

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Complex Relationship between Obesity and the Fat Mass and Obesity Locus

The Mediterranean diet (MeD) plays a key role in the prevention of obesity. Among the genes involved in obesity, the Fat mass and obesity-associated gene (FTO) is one of the most known, but its interaction with MeD remained uncertain so far. We carried out a study on a sample of 188 Italian subjects, analyzing their FTO rs9939609 alleles, and the difference in body composition between the baseline and a 4-weeks nutritional intervention. The sample was divided into two groups: the control group of 49 subjects, and the MeD group of 139 subjects. We found significant relations between MeD and both variation of total body fat (ΔTBFat) (p = 0.00) and gynoid body fat (p = 0.04). ∆TBFat (kg) demonstrated to have a significant relation with the interaction diet-gene (p = 0.04), whereas FTO was associated with the variation of total body water (p = 0.02). MeD demonstrated to be a good nutritional treatment to reduce the body fat mass, whereas data about FTO remain uncertain. Confirming or rejecting the hypothesis of FTO and its influence on body tissues during nutritional treatments is fundamental to decide whether its effect has to be taken into consideration during both development of dietetic plans and patients monitoring. Trial Registration ClinicalTrials.gov Id: NCT01890070. Registered 01 July 2013, https://clinicaltrials.gov/ct2/show/NCT01890070

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Influence of FTO rs9939609 and Mediterranean diet on body composition and weight loss: a randomized clinical trial.

Background/aim: The aim of this study is to find the association between diabetic microvascular complications and the neutrophil-to-lymphocyte ratio (NLR) in subjects with type 2 diabetes. Materials and methods: This was a retrospective study based on hospital data records from January 2005 to May 2016 at the Baqai Institute of Diabetology and Endocrinology. The eligibility criteria included subjects with type 2 diabetes with their latest complete blood count while subjects with conditions such as chronic inflammation, cancer, heart failure, and end-stage renal disease were not eligible for inclusion. Subjects were divided into two groups: one with any microvascular complications and the other with no microvascular complications. Body mass index, anthropometric measurements, and blood pressure were measured. Results: Out of 5620 type 2 diabetic subjects, 3202 (57%) were male and (2418) 43% were female. Among these, 3374 diabetic subjects had one or more microvascular complications and 2246 had no microvascular complications. The NLR was found to be 1.14 times higher in diabetic subjects with at least one microvascular complication as compared to diabetic subjects without any complications (4.34 ± 3.32 vs. 3.36 ± 2.67; P < 0.0001). Factors likely associated with microvascular complications were high levels of NLR, HbA1c, serum creatinine, and systolic blood pressure and longer duration of diabetes. Conclusion: According to the results, the NLR is an efficient, cheaper, and readily available marker of inflammation and it is known as an important predictor for the existence of microvascular complications in subjects with type 2 diabetes.

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Neutrophil-to-lymphocyte ratio and microvascular complications in subjects with type 2 diabetes: Pakistan’s perspective

OBJECTIVE To determine the association of SNP in FTO gene, rs9939609, with Metabolic Syndrome (MS) in type 2 diabetic subjects at a tertiary care unit of Karachi, Pakistan. METHODS We genotyped FTO rs9939609 SNP in 296 patients with type 2 diabetes from the Out Patient Department (OPD) of Baqai Institute of Diabetology and Endocrinology (BIDE). MS was defined on the basis of International Diabetes Federation (IDF) and National Cholesterol Education program (NCEP) criterion. Association between the rs9939609 SNP and MS was tested through chi-square and Z-tests by using odds ratio (OR) with 95% confidence intervals. RESULTS The frequency of MS as defined by IDF criterion was significantly higher in female subjects as compared to male subjects (p= 0.006). Carriers of ≥ 1 copy of the rs9939609 A allele were significantly more likely to had MS (69.6%) than non-carriers (30.4%), corresponding to a carrier odds ratio (OR) of 0.52 (95% confidence interval [CI] (0.29-0.93), with a similar trend for the ATP III-defined MS."A" allele carriers under dominant model, carry all the criterion of MS more significantly as compared to non-carriers. CONCLUSION The FTO rs9939609 SNP was associated with an increased risk for Metabolic Syndrome in type 2 diabetic populations at a tertiary care unit of Karachi, Pakistan.

Association of SNP rs9939609 in FTO gene with metabolic syndrome in type 2 diabetic subjects, rectruited from a tertiary care unit of Karachi, Pakistan.

Aim To determine the effect of genetic variants within the FTO gene (rs9939609) on obesity related traits and type 2 diabetes in South Asian population of Karachi, Pakistan Methods A case-control study was conducted at Baqai Institute of Diabetology and Endocrinology (BIDE), Baqai Medical University situated in Karachi A total of 296 patients with known type 2 diabetes and 198 controls aged greater than and equal to 45 years were recruited The Anthropometric, clinical and biochemical data was collected on a structured questionnaire Single nucleotide polymorphism (SNP) in FTO gene was identified by Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR) Association between the single nucleotide polymorphism and categorical variables such as type 2 diabetes and obesity category was tested through logistic regression analysis Results We observed a strong association of the minor allele A at rs9939609 with type 2 diabetes Significant difference was observed in frequency of FTO genotype when diabetic subjects were compared with controls in co dominant, dominant and recessive models This association remained significant even after adjusting for body mass index (BMI) and for waist circumference The frequency of homozygous risk Alleles (AA) was found to be higher in obese & overweight (≥23 kg/m 2 ) and females with central obesity in our study population The association of FTO variant with BMI and central obesity does not reach to statistical significance Conclusion In the study population of South Asian ancestry, variants of the FTO gene predispose to type 2 diabetes, but not entirely through their effect on BMI

Common variant within the FTO gene, rs9939609, obesity and type 2 diabetes in population of Karachi, Pakistan

Aim Glycated hemoglobin (HbA1c) cut-off values as diagnostic tool in diabetes and prediabetes with its concordance to oral glucose tolerance test (OGTT) in Pakistani population. Methodology Data for this substudy was obtained from second National Diabetes Survey of Pakistan (NDSP) 2016–2017. With this survey, 10 834 individuals were recruited and after excluding known subjects with diabetes, 6836 participants fulfilled inclusion criteria for this study. Demographic, anthropometric and biochemical parameters were obtained. OGTT was used as standard diagnostic tool to screen population and HbA1c for optimal cut-off values. Participants were categorized into normal glucose tolerance (NGT), newly diagnosed diabetes (NDD) and prediabetes. Results Out of 6836 participants, 4690 (68.6%) had NGT, 1333 (19.5%) had prediabetes and 813 (11.9%) had NDD by OGTT criteria with median (IQR) age of 40 (31–50) years. Optimal HbA1c cut-off point for identification of diabetes and prediabetes was observed as 5.7% ((AUC (95% CI)=0.776 (0.757 to 0.795), p Conclusion Findings from second NDSP demonstrated disagreement between findings of OGTT and HbA1c as diagnostic tool for Pakistani population. As compared with international guidelines, HbA1c threshold for prediabetes and NDD were lower in this part of world. HbA1c as diagnostic tool might require ethnic or regional-based modification in cut-off points, validated by relevant community-based epidemiological surveys.

https://drc.bmj.com/content/bmjdrc/8/1/e001058.full.pdf

Glycated hemoglobin (HbA1c) as diagnostic criteria for diabetes: the optimal cut-off points values for the Pakistani population; a study from second National Diabetes Survey of Pakistan (NDSP) 2016-2017.

OBJECTIVE To assess the 10-year risk of coronary artery disease (CAD) in subjects with impaired glucose tolerance (IGT) using Framingham risk score. METHODS Data for this study was collected from Diabetes Prevention and Awareness Program. Primary prevention team visited different primary health care centers, factories, service organizations and offices within Karachi, Pakistan. IGT was diagnosed according to World Health Organization criteria after taking informed consent. Information regarding social-demography, dietary habits and physical activities were obtained by a designed questionnaire on one-to-one based interview. Framingham risk score (FRS) was used to assess risk of developing CAD. RESULTS A total of 315 subjects with IGT were recruited for the study. Mean age of subjects was 44.1 ± 9.8 years and mean BMI was 27.3 ± 5.0 kg/m2. Overall, 31.4% of the participants were at risk of having CAD. Males were 6.4 times and hypertensive subjects were 2.44 times more likely to have CAD in next 10 years. CONCLUSION According to the findings of the study, male and hypertensive IGT subjects were more likely to develop CAD in next 10 years. Community based awareness programs are needed to educate people regarding healthy lifestyle in order to reduce the risk of IGT and CAD.

Iftikhar Ahmed Siddiqui

Papers

Neutrophil-to-lymphocyte ratio and microvascular complications in subjects with type 2 diabetes: Pakistan’s perspective

Association of SNP rs9939609 in FTO gene with metabolic syndrome in type 2 diabetic subjects, rectruited from a tertiary care unit of Karachi, Pakistan.

Common variant within the FTO gene, rs9939609, obesity and type 2 diabetes in population of Karachi, Pakistan

Glycated hemoglobin (HbA1c) as diagnostic criteria for diabetes: the optimal cut-off points values for the Pakistani population; a study from second National Diabetes Survey of Pakistan (NDSP) 2016-2017.

Framingham risk score in impaired glucose tolerant population: A sub analysis of Diabetes Prevention and Awareness Program of Pakistan.