Common Drug Pipelines for the Treatment of Diabetic Nephropathy and Hepatopathy: Can We Kill Two Birds with One Stone?

Type 2 diabetes (T2D) is associated with diabetic nephropathy as well as nonalcoholic steatohepatitis (NASH), which can be called "diabetic hepatopathy or diabetic liver disease". NASH, a severe form of nonalcoholic fatty disease (NAFLD), can sometimes progress to cirrhosis, hepatocellular carcinoma and hepatic failure. T2D patients are at higher risk for liver-related mortality compared with the nondiabetic population. NAFLD is closely associated with chronic kidney disease (CKD) or diabetic nephropathy according to cross-sectional and longitudinal studies. Simultaneous kidney liver transplantation (SKLT) is dramatically increasing in the United States, because NASH-related cirrhosis often complicates end-stage renal disease. Growing evidence suggests that NAFLD and CKD share common pathogenetic mechanisms and potential therapeutic targets. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors are expected to ameliorate NASH and diabetic nephropathy/CKD. There are no approved therapies for NASH, but a variety of drug pipelines are now under development. Several agents of them can also ameliorate diabetic nephropathy/CKD, including peroxisome proliferator-activated receptors agonists, apoptosis signaling kinase 1 inhibitor, nuclear factor-erythroid-2-related factor 2 activator, C-C chemokine receptor types 2/5 antagonist and nonsteroidal mineral corticoid receptor antagonist. This review focuses on common drug pipelines in the treatment of diabetic nephropathy and hepatopathy.

Evaluation of postprandial hypoglycemia in patients with nonalcoholic fatty liver disease by oral glucose tolerance testing and continuous glucose monitoring.

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is often associated with insulin resistance and glucose intolerance. Postprandial hypoglycemia frequently occurs in NAFLD patients; however, the details remain unclear. PATIENTS AND METHODS: The 75-g oral glucose tolerance test (75gOGTT) in 502 patients with biopsy-proven NAFLD and continuous glucose monitoring (CGM) in 20 patients were performed, and the characteristics and causes of postprandial hypoglycemia were investigated. RESULTS: The proportion of patients in the Hypo subgroup [plasma glucose (PG) at 180 min

High fasting insulin concentrations may be a pivotal predictor for the severity of hepatic fibrosis beyond the glycemic status in non-alcoholic fatty liver disease patients before development of diabetes mellitus.

BACKGROUND: Insulin resistance and type 2 diabetes mellitus (T2DM) contribute to the progression of non-alcoholic fatty liver disease (NAFLD). However, the relationship between glucose metabolic factors and the histological severity in NAFLD patients before development of T2DM is not well known. METHODS: In 103 biopsy-proven NAFLD patients (68 men and 35 women) with hemoglobin A1c of <6.5% and fasting blood glucose of <126 mg/dL, we investigated whether glucose metabolic factors influenced the severity of hepatic fibrosis without prior known T2DM. RESULTS: Female gender, age, serum aspartate aminotransferase, the aspartate aminotransferase/alanine aminotransferase ratio, fasting immunoreactive insulin (f-IRI), homeostasis model assessment - insulin resistance, hemoglobin A1c, hyaluronic acid, and type IV collagen 7 s were significantly higher, and 1,5-anhydroglucitol was significantly lower, in the fibrosis stage F3 group than in the F0-2 group. Multiple logistic regression analysis showed that only f-IRI (P = 0.006; odds ratio, 1.15151; 95% confidence interval, 1.04198-1.27254) was significantly indicated as a predictive factor for F3. As determined by both forward and backward stepwise selection analyses to optimize the model, f-IRI (P = 0001; odds ratio, 1.16788) remained an independent predictive factor for F3. To discriminate the F3 group from the F0-2 group, the area under the receiver operating characteristic curves showed that fasting insulin was 0.7219, and the best cut-off value of f-IRI was 13.2 µU/mL in the receiver operating characteristic curve analysis. CONCLUSIONS: High fasting insulin concentrations may be a pivotal glucose metabolic predictor for the severity of hepatic fibrosis beyond the glycemic status in NAFLD patients before development of T2DM.

Glycemic variability is an independent predictive factor for development of hepatic fibrosis in nonalcoholic fatty liver disease.

UNLABELLED: Patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) often have metabolic disorders including insulin resistance and type 2 diabetes mellitus (T2DM). We clarified the predictive factors in glucose metabolism for progression of hepatic fibrosis in patients with NAFLD by the 75-g oral glucose tolerance test (75gOGTT) and a continuous glucose monitoring system (CGMS). One hundred sixty-nine patients (68 female and 101 male patients) with biopsy-proven NAFLD with performance with 75gOGTT were enrolled and divided into four groups according to the stage of hepatic fibrosis (F0-3). The proportion of patients with T2DM significantly gradually increased, HbA1c and the homeostasis model assessment of insulin resistance were significantly elevated, and 1,5-anhydroglucitol (1,5-AG) was remarkably decreased with the progression of fibrosis. In the 75gOGTT, both plasma glucose and insulin secretion were remarkably increased with the progression of fibrosis. The only factor significantly associated with advanced fibrosis was 1,5-AG (P = 0.008) as determined by multivariate logistic regression analysis. We next evaluated the changes in blood glucose during 24 hours by monitoring with the CGMS to confirm the relationship between glycemic variability and progression of fibrosis. Variability of median glucose, standard deviation of median glucose (P = 0.0022), maximum blood glucose (P = 0.0019), and ΔMin-max blood glucose (P = 0.0029) were remarkably higher in severe fibrosis than in mild fibrosis. CONCLUSION: Hyperinsulinemia and hyperglycemia, especially glycemic variability, are important predictive factors in glucose impairment for the progression of hepatic fibrosis in NAFLD.

Usefulness of Technetium-99 m-2-methoxy-isobutyl-isonitrile liver scintigraphy for evaluating disease activity of non-alcoholic fatty liver disease.

AIM: Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD). Therefore, it is important to evaluate disease activity and distinguish NASH from simple steatosis in NAFLD. Technetium-99 m-2-methoxy-isobutyl-isonitrile ((99m) Tc-MIBI) is a lipophilic cation designed for myocardial perfusion scintigraphy in the diagnosis of ischemic heart diseases, and its retention reflects mitochondrial function. It was reported that hepatic mitochondrial abnormalities would be an important predictive factor for NASH disease progression. The aim of this study was to examine the clinical usefulness of (99m) Tc-MIBI liver scintigraphy for evaluating disease activity of NAFLD and distinguishing NASH from simple steatosis in patients with NAFLD. METHODS: Twenty-six patients with biopsy-proven NAFLD were enrolled. Clinicolaboratory tests and (99m) Tc-MIBI liver scintigraphy were performed. To evaluate hepatic uptake, regions of interest were set at the liver and heart, and the uptake ratio of the liver to heart (liver/heart ratio) was calculated. RESULTS: All patients with NAFLD were classified into three groups according to the NAFLD activity score: non-NASH (simple steatosis) (n = 4), borderline NASH (n = 11), and NASH (n = 11). Liver/heart ratios were significantly lower in NASH than in simple steatosis (P < 0.05). Moreover, liver/heart ratios were significantly correlated with NAFLD activity scores among the patients (r = -0.413, P < 0.05). CONCLUSIONS: The present study indicates that (99m) Tc-MIBI liver scintigraphy would be a useful non-invasive functional imaging method with which to evaluate disease activity of NAFLD and distinguish NASH from simple steatosis.

Angiotensinogen gene haplotype is associated with the prevalence of Japanese non-alcoholic steatohepatitis.

AIM: Non-alcoholic steatohepatitis (NASH) patients frequently have hypertension, which is considered to be an important predictive factor for the subsequent development of hepatic fibrosis. The renin-angiotensin system is also known to contribute to the progression of NASH. Various types of functional single-nucleotide polymorphisms (SNPs) involved in the development of NASH have been proposed. Angiotensinogen (AGT) gene SNPs related to cardiovascular diseases have been reported. We aimed to evaluate the involvement of the AGT gene haplotype in Japanese NASH patients. METHODS: Previously described genotypes of SNPs of the AGT gene, rs4762 C/T polymorphism (T207M), rs699 C/T polymorphism (T268M), and rs7079 C/A polymorphism (C11537A), were determined in 124 Japanese biopsy-proven NASH patients and 150 healthy volunteers (controls). RESULTS: The allele and genotype frequencies in rs4762 and rs699 SNPs in NASH patients were similar to those in controls, while the frequency of the A allele and A/- genotype in rs7079 SNPs were much higher in NASH patients than in controls. In addition, the 3-SNP haplotype CTA was significantly over-represented in NASH patients compared with controls. Regarding clinical features of NASH patients, diastolic blood pressures in patients with the CTA/- genotype were much higher than in patients with other genotypes. CONCLUSIONS: We found a 3-SNP haplotype of the AGT gene that is involved in the development of NASH and influences hypertension in NASH patients. These results provide new insight into the therapy of NASH patients with the CTA haplotype using ACE inhibitors or angiotensin II type 1 receptor blockers.