Name Sequence Exon 2 mG6pc S 5’-TCCCTGTCACCTGTGAG-3’ Exon 5 mG6pc AS 5’-CACAAGAAGTCTTTGTAA-3’ Exon1 mG6pcS 5’-TTACCAAGACTCCCAGGACTG-3’ Exon2 mG6pcAS 5’-GAGCTGTTGCTGTAGTAGTCG-3’ Pck1S 5’-AGCCTTTGGTCAACAACTGG-3’ Pck1AS 5’-TGCCTTCGGGGTTAGTTATG-3’ GcgR S 5’-ACCCAACTATTGCTGGTTGC-3’ GcgR AS 5’-CCATGTTGTCATTGCTGGTC-3’ Hmgcs2 S 5’-CCGTATGGGCTTCTGTTCAG-3’ Hmgcs2 AS 5’-AGCTTTGTGCGTTCCATCAG-3’ mL19S 5’-AGAAGATTGACCGCCATAT-3’ mL19AS 5’-TTCGTGCTTCCTTGGTCTTAGA-3’ CRU G6pc S 5’-TTTGCTATTTTACGTAAATCACCCT-3’  CRU G6pc AS 5’-GTACCTCAGGAAGCTGCCA-3’ CRU Pck1 S 5’-GGCCTCCCAACATTCATTAAC-3’ CRU Pck1 AS 5’-GTAGCTAGCCCTCCTCGCTTTAA-3’ GRU G6pc S 5’-CACCCCTTAGCACTGTAAGCCGTGTG-3’ GRU G6pc AS 5’-GGATTCAGTCTGTAGGTCAACCTAGCCC-3’ GRU Pck1 S 5’-TGCAGCCAGCAACATATGAA-3’

Supplementary table 1

Thyroid dysfunction and diabetes mellitus are closely linked. Several studies have documented the increased prevalence of thyroid disorders in patients with diabetes mellitus and vice versa. This review critically discusses the different underlying mechanisms linking type 1 and 2 diabetes and thyroid dysfunction to demonstrate that the association of these two common disorders is unlikely a simple coincidence. We assess the current state of knowledge on the central and peripheral control of thyroid hormone on food intake and glucose and lipid metabolism in target tissues (such as liver, white and brown adipose tissue, pancreatic β cells, and skeletal muscle) to explain the mechanism linking overt and subclinical hypothyroidism to type 2 diabetes and metabolic syndrome. We also elucidate the common susceptibility genes and the pathogenetic mechanisms contributing to the autoimmune mechanism involved in the onset of type 1 diabetes mellitus and autoimmune thyroid disorders. An untreated thyroid dysfunction can impair the metabolic control of diabetic patients, and this association can have important repercussions on the outcome of both of these disorders. Therefore, we offer recommendations for the diagnosis, management, and screening of thyroid disorders in patients with diabetes mellitus, including the treatment of diabetic patients planning a pregnancy. We also discuss the major causes of failure to achieve an optimal management of thyroid dysfunction in diabetic patients and provide recommendations for assessing and treating these disorders during therapy with antidiabetic drugs. An algorithm for a correct approach of these disorders when linked is also provided.

Thyroid Dysfunction and Diabetes Mellitus: Two Closely Associated Disorders.

2019 Global NAFLD Prevalence: A Systematic Review and Meta-analysis

Diabetic complications may be associated with impaired time-dependent glycemic control. Therefore, long-term glycemic variability, assessed by variations in haemoglobin A1c (HbA1c), may be a potential risk factor for microvascular complications, such as diabetic peripheral neuropathy (DPN). We investigated the association of HbA1c variability with DPN in patients with type 2 diabetes. In this cross-sectional study, 563 type 2 diabetic patients who had been screened for DPN and undergone quarterly HbA1c measurements during the year preceding enrolment were recruited. DPN was confirmed in patients displaying both clinical manifestations of neuropathy and abnormalities in a nerve conduction evaluation. HbA1c variability was assessed by the coefficient of variation of HbA1c (CV-HbA1c), and the mean of HbA1c (M-HbA1c) was calculated. In addition, medical history and clinical data were collected. Among the recruited patients, 18.1% (n = 102) were found to have DPN, and these patients also presented with a higher CV-HbA1c than the patients without DPN (p < 0.001). The proportion of patients with DPN increased significantly from 6.9% in the first to 19.1% in the second and 28.5% in the third tertile of CV-HbA1c (p for trend < 0.001). After adjusting for initial HbA1c, M-HbA1c and other clinical factors via multiple logistic regression analysis, the odds ratios (ORs) for DPN in the second and third versus those in the first CV-HbA1c tertile were 3.61 (95% CI 1.62–8.04) and 6.48 (2.86–14.72), respectively. The area under the receiver operating characteristic (ROC) curve of CV-HbA1c was larger than that of M-HbA1c, at 0.711 (95% CI 0.659–0.763) and 0.662 (0.604–0.721), respectively. ROC analysis also revealed that the optimal cutoff value of CV-HbA1c to indicate DPN was 15.15%, and its corresponding sensitivity and specificity were 66.67% and 65.73%, respectively. Increased HbA1c variability is closely associated with DPN in type 2 diabetic patients and could be considered as a potent indicator for DPN in these patients.

/pdf/hba1c-variability-and-diabetic-peripheral-neuropathy-in-type-3ghns362p7.pdf

HbA1c variability and diabetic peripheral neuropathy in type 2 diabetic patients.

There has been a growing interest in the role of vitamin E supplementation in the treatment and/or prevention of nonalcoholic fatty liver (NAFLD). We performed a systematic review of the medical literature from inception through 15 June 2018 by utilizing PubMed and searching for key terms such as NAFLD, vitamin E, alpha-tocopherol, and nonalcoholic steatohepatitis (NASH). Data from studies and medical literature focusing on the role of vitamin E therapy in patients with NAFLD and nonalcoholic steatohepatitis (NASH) were reviewed. Most studies assessing the impact of vitamin E in NAFLD were designed to evaluate patients with NASH with documented biochemical and histological abnormalities. These studies demonstrated improvement in biochemical profiles, with a decline in or normalization of liver enzymes. Furthermore, histological assessment showed favorable outcomes in lobular inflammation and hepatic steatosis following treatment with vitamin E. Current guidelines regarding the use of vitamin E in the setting of NAFLD recommend that vitamin E-based treatment be restricted to biopsy-proven nondiabetic patients with NASH only. However, some concerns have been raised regarding the use of vitamin E in patients with NASH due to its adverse effects profile and lack of significant improvement in hepatic fibrosis. In conclusion, the antioxidant, anti-inflammatory, and anti-apoptotic properties of vitamin E accompanied by ease-of-use and exceptional tolerability have made vitamin E a pragmatic therapeutic choice in non-diabetic patients with histologic evidence of NASH. Future clinical trials with study design to assess vitamin E in combination with other anti-fibrotic agents may yield an additive or synergistic therapeutic effect.

https://www.mdpi.com/2079-9721/6/4/86/pdf

The Role of Vitamin E in the Treatment of NAFLD

Several studies have suggested that bilirubin, a potent innate antioxidant, plays a protective role against cardiovascular and microvascular disease This study investigated the association between serum concentrations of total bilirubin (TB) and the presence of diabetic peripheral neuropathy (DPN) in Korean diabetic patients This cross-sectional study involved 1207 patients aged more than 30 years with type 2 diabetes DPN was assessed according to clinical symptoms and physical examinations using Michigan Neuropathy Screening Instrument examination score, 10-g monofilament sensation, and current perception threshold The subjects were stratified into gender-specific tertiles based on TB values, and the relationship between the TB values and DPN was analyzed Compared with patients within the lowest TB tertile, those with higher TB levels consisted of patients with shorter duration of diabetes, lower HbA1c, better renal function, and less autonomic neuropathy, retinopathy, and albuminuria Serum TB levels were inversely associated with DPN In multivariate analysis for the development of DPN after adjusting for potential confounding factors including retinopathy, albuminuria, and autonomic neuropathy, the TB levels were inversely associated with the presence of DPN, both as a continuous variable [odds ratio (OR) per log standard deviation (SD) 079; 95% confidence interval (CI) 065-097; P = 0022] and when categorized in tertiles (the highest vs the lowest tertile; OR 063; 95% CI 040-099; P = 0046) Low serum bilirubin levels are significantly associated with DPN, independently of classic risk factors and other microvascular complications Further investigation is necessary to determine whether serum bilirubin has a prognostic significance on DPN

Inverse association between serum total bilirubin levels and diabetic peripheral neuropathy in patients with type 2 diabetes.

We investigated whether thyroid function could identify obesity phenotype in euthyroid subjects. A cross-sectional analysis was performed among nondiabetic, euthyroid subjects. We stratified subjects into four groups by BMI and insulin resistance (IR). Of 6241 subjects, 33.8% were overweight or obese (OW/OB) and 66.2% were normal weight (NW). Free thyroxine (FT4) levels were negatively associated with body mass index, waist circumference, triglyceride, c-reactive protein, and HOMA-IR and positively with high-density lipoprotein cholesterol in both genders. In multivariate regression analysis, FT4 level, a continuous measurement, was negatively correlated with HOMA-IR (β = -0.155, P < 0.001 in men; β = -0.175, P < 0.001 in women). After adjustment for age, sex, metabolic, and life style factors, subjects in the lowest FT4 quartile had an odds ratio (OR) for IR of 1.99 (95% confidence interval 1.61-2.46), as compared to those in the highest quartile. The association between low FT4 and IR remained significant in both NW and OW/OB subgroups. In conclusion, low normal FT4 levels were independently related to IR in NW and OW/OB euthyroid subjects. Further studies are needed to investigate the mechanisms by which low FT4 levels are linked to high IR in euthyroid ranges.

/pdf/association-between-lower-normal-free-thyroxine-4jmwnky7m1.pdf

Association between Lower Normal Free Thyroxine Concentrations and Obesity Phenotype in Healthy Euthyroid Subjects.

Background
Considerable evidence suggests that bilirubin is a potent physiologic antioxidant that may provide important protection against cardiovascular disease (CVD) and inflammation. We investigated the relationship between serum total bilirubin (TB) levels and arterial stiffness, measured by the brachial-ankle pulse wave velocity (baPWV), in patients with type 2 diabetes.

/pdf/inverse-association-between-serum-bilirubin-levels-and-22x4ciljb7.pdf

Inverse Association between Serum Bilirubin Levels and Arterial Stiffness in Korean Women with Type 2 Diabetes

Background and Aim

Growing evidence suggests that non-alcoholic fatty liver disease (NAFLD) is interrelated with renal dysfunction and disturbed bone metabolism, both of which play a key role in calcium and phosphorus homeostasis. We investigated the association between NAFLD and serum calcium and phosphorus levels in Korean subjects.



Methods

We performed a cross-sectional analysis of 16 592 subjects undergoing a general health checkup. NAFLD was assessed based on ultrasonographically detected fatty liver in the absence of excessive alcohol consumption and other causes of liver disease.



Results

The proportion of the population with fatty liver detected by ultrasonography was 43.2% for males and 17.6% for females. We observed that a higher serum albumin-corrected calcium (Cac) level was associated with smoking, hypertension, and unfavorable metabolic parameters in both genders, but the serum phosphorus levels showed an inconsistent correlation with metabolic abnormalities. After adjusting for age, gender, waist circumference, body mass index, smoking status, exercise, diabetes, hypertension, lipid profiles, and renal function, serum Cac, phosphorus, and Cac-phosphorus products were independent risk factors for fatty liver (odds ratio [OR]: 1.71, 95% confidence interval [CI]: 1.49–1.95, P < 0.001; OR: 1.34, 95% CI: 1.22–1.48, P < 0.001; and OR: 1.20, 95% CI: 1.14–1.26, P < 0.001, respectively), and the risk of fatty liver increased in a graded manner over the quartiles.



Conclusion

Serum calcium and phosphorus levels are significantly associated with NAFLD. Further investigation is needed to verify whether calcium and phosphorus levels indicate a higher risk of NAFLD.

Association between serum calcium and phosphorus concentrations with non-alcoholic fatty liver disease in Korean population.

Background
This study investigated the association between serum gamma-glutamyltransferase (GGT) level and subclinical atherosclerosis in patients with type 2 diabetes.

/pdf/serum-gamma-glutamyltransferase-is-not-associated-with-3l7t6xb7c2.pdf

Eun Young Mo

Papers

Inverse association between serum total bilirubin levels and diabetic peripheral neuropathy in patients with type 2 diabetes.

Association between Lower Normal Free Thyroxine Concentrations and Obesity Phenotype in Healthy Euthyroid Subjects.

Inverse Association between Serum Bilirubin Levels and Arterial Stiffness in Korean Women with Type 2 Diabetes

Association between serum calcium and phosphorus concentrations with non-alcoholic fatty liver disease in Korean population.

Serum gamma-glutamyltransferase is not associated with subclinical atherosclerosis in patients with type 2 diabetes.