Early Onset Of Diabetes Mellitus Research Articles

MitoTEMPOL modulates mitophagy and histopathology of Wistar rat liver after streptozotocin injection.

This study aims to explore the effect of mitoTEMPOL on histopathology, lipid droplet, and mitophagy gene expression of Wistar rat's liver after injection of streptozotocin (STZ). Twenty male Wistar rats were divided into 4 groups: Control (n=5); 100 mg/kg BW/day mitoTEMPOL orally (n=5); 50 mg/kg BW STZ intraperitoneal injection (n=5); and mitoTEMPOL+STZ (n=5). STZ was given a single dose, while mitoTEMPOL was given for 5 weeks after 1 week of STZ injection. Histopathological appearance, lipid droplets, mitophagy, and autophagy gene expression were examined after the mitoTEMPOL treatment. We found metabolic zone shifting that might be correlated with the liver activity of fatty acid oxidation in the STZ group, a decrease of lipid droplets in mitoTEMPOL and mitoTEMPOL + STZ compared with Control and STZ groups were found in this study. We also found significant changes in PINK1, Parkin, BNIP3, Mfn1, and LC3 gene expression, but no difference in Opa1, Fis1, Drp1, and p62 gene expression, suggesting a change of mitochondrial fusion rather than mitochondrial fission correlated with mitophagy. All this concluded that mitoTEMPOL could act as a modulator of mitophagy and metabolic function of the liver, thus amplifying its crucial role in preventing mitochondrial damage in the liver in the early onset of diabetes mellitus.

Severe Wolfram Syndrome Caused by a Novel Frameshift Mutation in <i>WFS1</i> Gene: Effect on the WFS1/CaM Interaction and Phenotype-Genotype Correlation

Mutations in the WFS1 gene have been reported in Wolfram syndrome (WFS), a rare and autosomal recessive disorder defined by early onset of diabetes mellitus and progressive optic and hearing impairment. Only few data are available concerning the association between clinical and molecular aspects of the WFS. We present a consanguineous family with a patient presenting an early onset of WFS and severe manifestations. Sequencing of WFS1 gene was performed for all the family members to search for responsible mutation and bioinformatics tools were conducted to predict its effect on structure and function of the protein. We have detected a novel frameshift mutation in the proband at homozygous state and at the heterozygous state in the parents who have no WFS manifestations. In silico analysis predicted the pathogenicity of the mutation and could lead to a complete loss of its function. Thus, 3D modeling showed that the mutation abolishes the interaction of the CaM binding region to the N-terminal of WFS1 and then impairs the WFS1-CaM complex formation. Genotype-phenotype correlation study shows that the novel mutation predisposes to early onset of diabetes and severe symptoms observed in the proband. We also report the effect of the frameshift mutation on the CaM-WFS1 impaired binding, and we discuss its possible consequence in pancreatic β-cells dysfunction and its role in the early onset of diabetes. In conclusion, the combination of impaired functions of WFS1 including unproper interaction of the CaM, Ca2+ uptake, mitochondrial dysfunction, and apoptosis under the ER stress could be involved in the severe phenotype and early onset of WFS of our patient.

Risk factors for development of endocrine insufficiency in chronic pancreatitis

Endocrine insufficiency is a common and frequent complication of chronic pancreatitis. Identifying the role of pancreatic damage in the development of diabetes is important for early identification and appropriate management. MethodsAll consecutive CP patients between January 2019 and May 2020 were retrospectively studied. Relevant statistical tests were performed. A two sided p value < 0.05 was considered statistically significant. ResultsTotal 587 chronic pancreatitis patients were included of which 118 (20.1%) patients developed diabetes with duration of 12 (IQR 4–48) months. Older age (OR 1.079; 95% CI 1.045–1.113; p < 0.001), presence of pancreatic parenchymal (OR 2.284; 95% CI 1.036–5.038; p = 0.041) and ductal (OR 2.351; 95% CI 1.062–5.207; p = 0.035) calcifications, exocrine insufficiency (OR 6.287; 95% CI 2.258–17.504; p < 0.001), and pancreatic duct stricture (OR 3.358; 95% CI 1.138–9.912; p = 0.028) were independently associated with development of diabetes mellitus in chronic pancreatitis patients. On cox-regression analysis, smoking (HR 2.370; 95% CI 1.290–4.354; p = 0.005) and pancreatic ductal calcification (HR 2.033; 95% CI 1.286–3.212; p = 0.002) were independently associated with earlier onset of diabetes mellitus in patients with chronic pancreatitis. ConclusionPancreatic calcification, pancreatic duct stricture and pancreatic exocrine insufficiency are associated with development of diabetes mellitus in chronic pancreatitis indicating disease progression. Smoking is the modifiable risk factors associated with early onset of diabetes mellitus in CP patients.

Unraveling LMNA Mutations in Metabolic Syndrome: Cellular Phenotype and Clinical Pitfalls.

This study details the clinical and cellular phenotypes associated with two missense heterozygous mutations in LMNA, c.1745G>T p.(Arg582Leu), and c.1892G>A p.(Gly631Asp), in two patients with early onset of diabetes mellitus, hypertriglyceridemia and non-alcoholic fatty liver disease. In these two patients, subcutaneous adipose tissue was persistent, at least on the abdomen, and the serum leptin level remained in the normal range. Cellular studies showed elevated nuclear anomalies, an accelerated senescence rate and a decrease of replication capacity in patient cells. In cellular models, the overexpression of mutated prelamin A phenocopied misshapen nuclei, while the partial reduction of lamin A expression in patient cells significantly improved nuclear morphology. Altogether, these results suggest a link between lamin A mutant expression and senescence associated phenotypes. Transcriptome analysis of the whole subcutaneous adipose tissue from the two patients and three controls, paired for age and sex using RNA sequencing, showed the up regulation of genes implicated in immunity and the down regulation of genes involved in development and cell differentiation in patient adipose tissue. Therefore, our results suggest that some mutations in LMNA are associated with severe metabolic phenotypes without subcutaneous lipoatrophy, and are associated with nuclear misshaping.

First and third trimester serum concentrations of adropin and copeptin in gestational diabetes mellitus and normal pregnancy

Gestational diabetes mellitus (GDM) is a metabolic disease diagnosed in 1.7% up to 11.6% pregnancies. The prevalence of adverse pregnancy outcome is significantly higher in the case of early onset of diabetes mellitus. Adropin is a hormone promoting carbohydrate oxidation over fat oxidation, and influence nitric oxide synthase. Copeptin is a cleavage product of the vasopressin precursor recently correlated with diabetes mellitus. The aim of the study was to determine maternal serum adropin and copeptin concentrations in women with early and late manifestation of GDM and to discuss their potential role as biochemical markers of insulin resistance. Case-control study on 58 pregnant Caucasian women. Serum levels of adropin and copeptin were assessed in patients with early onset (GDM1) and classical gestational diabetes mellitus (GDM2). Complications such as macrosomia and hypotrophy were evaluated. There was no significant difference between the study and the control group (age, BMI, parity). Fetal growth disturbance rate was 37.5% in GDM1, 11% in GDM2 and 6% in controls. Adropin concentration in GDM patients was significantly higher than in control group (p < 0.001), but there was no difference between GDM1 and GDM2 group. High serum concentration of adropin positively correlated with elevated HbA1c (p < 0.05). The groups did not differ in terms of copeptin serum concentration. High adropin serum concentration in GDM patients is associated with increased risk of fetal growth disturbances, possibly due to improper placentation. According to our prospective study, neither copeptin nor adropin serum concentration are useful to discriminate between early and late onset of gestational diabetes mellitus.

Early Onset of Diabetes Mellitus Accelerates Cognitive Decline in Japanese Patients with Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes

Approximately 80% of patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) carry the A3243G mutation in the mitochondrial tRNALeu (UUR) gene. Conversely, this mutation has also been identified as one of the most prevalent genetic abnormalities in patients with diabetes mellitus. Mitochondrial diabetes mellitus complicated with MELAS is relatively common, and 12.5% of patients with the A3243G mutation develop MELAS after being diagnosed with diabetes mellitus. However, the clinical impact of diabetes mellitus in MELAS patients remains unclear. Therefore, we retrospectively studied 14 Japanese MELAS patients with the A3243G mutation: three men and eleven women, with the mean age of 48.0 (± 15.4) years. Eight patients had been diagnosed with diabetes mellitus prior to the diagnosis of mitochondrial disease, and all of them were treated with insulin. The other six included four patients with concurrent diagnosis of diabetes and mitochondrial disease, one patient diagnosed with diabetes after the diagnosis of mitochondrial disease, and one patient without developing diabetes currently. We thus compared the patients' characteristics between those with and without early onset of diabetes mellitus. Cognitive decline (75.0% vs. 0%; p = 0.03) and poor glycemic control with severe hypoglycemic events (75.0% vs. 16.7%; p = 0.05) were more common in MELAS patients with a prior diagnosis of diabetes than in those without the prior diagnosis of diabetes. Our data suggest that the latent progress of cognitive decline is accelerated because of early onset of diabetes mellitus in MELAS patients.

Effects of the extract from roasted chicory (Cichorium intybus L.) root containing inulin-type fructans on blood glucose, lipid metabolism, and fecal properties

The extract from roasted chicory (Cichorium intybus L.; 菊苣 jú jù) root (chicory root extract), which contains inulin-type fructans, has favorable effects including antihyperglycemic and antidyslipidemic effects and the improvement of bowel movement. In this study, we examined the effects of chicory root extract on blood glucose, lipid metabolism, and fecal properties in 47 healthy adult participants in a randomized, double-blind, placebo-controlled study. The participants were divided into a test group that drank chicory root extract and a placebo group that drank nonchicory root extract (ingesting 300 mL daily for 4 weeks). We performed hematological examinations and body composition measurements, and administered a visual analog scale (VAS) questionnaire for fecal properties at the baseline (Week 0) and after the intervention (Week 4) for the two groups. Although no significant differences in fasting plasma glucose or insulin were observed, hemoglobin A1c was found to decrease by ingesting chicory root extract. No intergroup differences in the levels of lipid metabolism parameters were observed. However, the level of adiponectin was significantly improved in the chicory root extract group when the baseline and postintervention values were compared. In addition, chicory root extract tends to improve the VAS score for fecal properties. These results suggest that chicory root extract could delay or prevent the early onset of diabetes mellitus and improve bowel movements.

Contribution of hyperglycemia on diabetic complications in obese type 2 diabetic SDT fatty rats: effects of SGLT inhibitor phlorizin.

The spontaneously diabetic torii (SDT) fatty rat is a new model of type 2 diabetes showing overt obesity, hyperglycemia and hyperlipidemia. With early onset of diabetes mellitus, diabetic microvascular complications, including nephropathy, peripheral neuropathy and retinopathy, are observed at young ages. In the present study, blood glucose levels of female SDT fatty rats were controlled with phlorizin, a non-selective SGLT inhibitor, to examine whether and how these complications are caused by hyperglycemia. Phlorizin treatment adequately controlled plasma glucose levels during the experiment. At 29 weeks of age, urinary albumin excretion considerably increased in SDT fatty rats. Glomerulosclerosis and tubular pathological findings also indicate diabetic nephropathy. These renal parameters tended to decrease with phlorizin; however, effects were partial. Sciatic nerve conduction velocities were significantly delayed in SDT fatty rats compared with Sprague-Dawley (SD) rats. Intraepidermal nerve fiber density, an indicator of subclinical small nerve fiber neuropathy, significantly decreased in SDT fatty rats. Retinal dysfunction (prolongation of peak latency for oscillatory potential in electroretinograms) and histopathological eye abnormalities, including retinal folding and mature cataracts were also observed. Both nerve and eye disorders were prevented with phlorizin. These findings indicate that severe hyperglycemia mainly causes diabetic complications in SDT fatty rats. However, other factors, such as hyperlipidemia and hypertension, may affect diabetic nephropathy. These characteristics of diabetic complications will become helpful in evaluating new drugs for diabetic complications using SDT fatty rats.

Dental caries and adolescents with type 1 diabetes

The aim of this study was to determine the prevalence of dental caries in adolescents with type 1 diabetes mellitus (DM). A clinical examination was carried out on 259 adolescents with type 1 DM as compared with 259 age- and sex-matched metabolically healthy controls. The DM cases were characterised by postprandial blood glucose and HBA1c levels, duration of the diseases, age at onset and level of control. Dental caries was assessed using the DMFT index. Data were analysed by Shapiro-Wilk's W, ANOVA, Student's t and Tukey's posthoc test. An intact dentition was found in none of the DM patients. DM adolescents had a higher mean DMFT score (p <0.001), fewer decayed (p <0.0001), and more filled (p <0.001) teeth than in the controls. In the well-controlled DM adolescents, the mean number of decayed (D) teeth was lower (p <0.0001) and the number of filled(F) teeth was higher than in patients with poorer glycaemic control. Early onset of DM was related to fewer decayed and filled teeth, but only if the oral hygiene was adequate (p <0.0001). Poor glycaemic control and the early onset of DM may increase the risk of dental caries, but appropriate oral hygiene together with satisfactory metabolic control may prevent the development of dental caries in adolescents with type 1 DM.

Increased OPG Expression and Impaired OPG/TRAIL Ratio in the Aorta of Diabetic Rats

Despite accumulating evidence showing that TNF-related apoptosis inducing ligand (TRAIL) plays a role in vascular biology and that its decoy receptor osteoprotegerin (OPG) is expressed in the vessel wall, modulation of these TNF and TNF-R family members in the early phases of diabetes mellitus has not been investigated. The expression of TRAIL and of OPG was examined both at the mRNA and protein levels in control and streptozotocin (SZT)-induced diabetic rats at early time points after the induction of diabetes mellitus. No differences in the steady-state mRNA levels of TRAIL were noticed by quantitative RT-PCR among the two groups of animals. On the other hand, diabetic rats showed a rapid and significant increase of the steady-state mRNA levels of OPG in the aortic wall of diabetic animals with respect to vehicle-treated (control) animals. These findings were confirmed at the protein level by analysing the amount of TRAIL and OPG proteins in aortic lysates by either Western blot or immunohistochemistry. Thus, an abnormal elevation of the OPG/TRAIL ratio in the vessel wall characterizes the early onset of diabetes mellitus and might represent a molecular mechanism involved in the vascular dysfunction characterizing diabetes mellitus.

Identification of novel mutations in WFS1 and genotype–phenotype correlation in Wolfram syndrome

Mutations in the WFS1 gene have been reported in Wolfram syndrome (WS), an autosomal recessive disorder defined by early onset of diabetes mellitus (DM) and progressive optic atrophy. Because of the low prevalence of this syndrome and the recent identification of the WFS1 gene, few data are available concerning the relationships between clinical and molecular aspects of the disease. Here, we describe 12 patients from 11 families with WS. We report on eight novel (A214fsX285, L293fsX303, P346L, I427S, V503fsX517, R558C, S605fsX711, P838L) and seven previously reported mutations. We also looked for genotype-phenotype correlation both in patients included in this study and 19 additional WS patients that were previously reported. Subsequently, we performed a systematic review and meta-analysis of five published clinical and molecular studies of WFS1 for genotype-phenotype correlation, combined with our current French patient group for a total of 96 patients. The presence of two inactivating mutations was shown to predispose to an earlier age of onset of both DM and optic atrophy. Moreover, the clinical expression of WS was more complete and occurred earlier in patients harboring no missense mutation.

An Increased Osteoprotegerin Serum Release Characterizes the Early Onset of Diabetes Mellitus and May Contribute to Endothelial Cell Dysfunction

Serum osteoprotegerin (OPG) is significantly increased in diabetic patients, prompting expanded investigation of the correlation between OPG production/release and glycemic levels. Serum levels of OPG, but not of its cognate ligand receptor activator of nuclear factor-kappaB ligand (RANKL), were significantly increased in type 2 diabetes mellitus patients compared with healthy blood donors. Serum OPG was also significantly elevated in a subgroup of recently diagnosed diabetic patients (within 2 years). The relationship between serum OPG and diabetes mellitus onset was next investigated in apoE-null and littermate mice. Serum OPG increased early after diabetes induction in both mouse strains and showed a positive correlation with blood glucose levels and an inverse correlation with the levels of free (OPG-unbound) RANKL. The in vitro addition of tumor necrosis factor-alpha to human vascular endothelial cells, but not human peripheral blood mononuclear cells, markedly enhanced OPG release in culture. In contrast, high glucose concentrations did not modulate OPG release when used alone or in association with tumor necrosis factor-alpha. Moreover, the ability of soluble RANKL to activate the extracellular signal-regulated kinase/mitogen-activated protein kinase and endothelial nitric-oxide synthase pathways in endothelial cells was neutralized by preincubation with recombinant OPG. Altogether, these findings suggest that increased OPG production represents an early event in the natural history of diabetes mellitus, possibly contributing to disease-associated endothelial cell dysfunction.

Wolfram syndrome in French population: Characterization of novel mutations and polymorphisms in theWFS1 gene

Wolfram syndrome (WS), a rare autosomal recessive neurodegenerative disorder, results in most cases from mutations in the WFS1 gene. In this study, a total of 19 patients with Wolfram syndrome and 36 relatives from 17 families were screened for mutations in the WFS1 gene. WFS1 mutations were identified on both alleles in 16 of 19 patients and on 1 allele of 3 patients, showing that WFS1 is the major gene involved in WS in the french population. We identified 25 different mutations, twelve of which were novel. We found 6 frameshift mutations, 6 nonsense mutations, 6 missense mutations, 6 in-frame deletions, and one new homozygous mutation in the splice donor site of exon 7 (c.861+1G>A) resulting in a frameshift. Most patients were compound heterozygotes. No common founder mutation or mutational hot spot were found in the WFS1 gene. Although most mutations occurred in exon 8, in some cases molecular screening requires analysis of all exons, including the non-coding exon 1. We also identified 3 new polymorphisms. Furthermore, genotype-phenotype correlation suggests that the presence of inactivating mutations on both alleles may be associated with an early onset of diabetes mellitus.

Increased oxidative stress in rat liver and pancreas during progression of streptozotocin-induced diabetes.

1. Oxygen free radicals have been suggested to be a contributory factor in complications of diabetes mellitus. There are many reports indicating the changes in parameters of oxidative stress in diabetes mellitus. In this study we aimed to identify whether oxidative stress occurs in the liver and pancreas in the initial stages of development of diabetes. 2. We therefore investigated the lipid peroxide level (thiobarbituric acid-reactive substances, TBARS) and activities of antioxidant enzymes [superoxide dismutase (SOD), catalase and glutathione peroxidase] in liver and pancreas of control and streptozotocin-induced diabetic rats at various stages of development of diabetes. 3. Male Sprague-Dawley rats were divided into two groups: group I, control (n = 42) and group II, diabetic (n = 42). Each group was further subdivided into seven groups consisting of six rats each. Rats in these subgroups were studied at weekly intervals (0 to 6 weeks). Plasma glucose levels, TBARS levels and activities of antioxidant enzymes were measured in liver and pancreas at various time intervals. 4. There was a significant (P < 0.05) and progressive increase in TBARS levels of liver and pancreas in the diabetic group. Total SOD and Cu-Zn-SOD activity increased (P < 0.05) with progression of diabetes while Mn-SOD activity showed no significant change in either tissue. Catalase and glutathione peroxidase activities increased significantly (P < 0.05) in liver and pancreas. 5. Immunohistochemical study of pancreatic islet revealed a decrease in the expression of insulin with progression of diabetes. However, glucagon and somatostatin showed an increase in immunoreactivity and a difference in their distribution pattern. 6. The findings of the present study suggest that oxidative stress starts at early onset of diabetes mellitus and increases progressively. In conclusion, the structural damage to these tissues or complications of diabetes mellitus may be due to oxidative stress.

Antioxidant defense system in diabetic kidney: a time course study.

Oxygen free radicals (OFRs) have been suggested to be a contributory factor in complications of diabetes mellitus. In the present study, we investigated the lipid peroxide level measured as thiobarbituric acid reactive substances (TBARS) and activities of antioxidant enzymes viz., [superoxide dismutase (SOD), catalase (CAT) and glutathione-peroxidase (GSH-Px)] in the kidney of streptozotocin induced diabetic rats at various stages of development of diabetes. Sprague Dawley rats were divided into two groups: group I, control (n = 42) and group II, diabetic (n = 42). Each group was further subdivided into seven groups each consisting of six rats. Rats in subgroups were studied at weekly intervals (0 to 6 weeks). Blood glucose levels were estimated at the time of sacrifice. TBARS levels and activity of antioxidant enzymes were measured in kidney. The levels of TBARS in the diabetic group increased initially, dropped to baseline level after 2 weeks and then progressively increased at 5th and 6th week (p < 0.05). There was an increase in catalase activity at first week after that it decreased as compared to control group. However, GSH-Px activity in the diabetic group increased after 1 week and then remained at the same level except a small drop in the 2nd week. Total SOD and CuZn-SOD activity increased significantly in diabetic kidney as compared to controls at all time intervals, while Mn-SOD activity showed no change. The present findings suggest that oxidative stress accompanies at early onset of diabetes mellitus and the susceptibility of the kidney to oxidative stress during the early stages may be an important factor in the development of diabetic nephropathy.

Time course study of oxidative stress in aorta and heart of diabetic rat.

1. Oxygen free radicals have been suggested to be a contributory factor in complications of diabetes mellitus. In the present study, we investigated the lipid peroxide level [thiobarbituric acid-reactive substances (TBARS)] and activities of antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase) in aorta, heart and blood of control and streptozotocin-induced diabetic rats at various stages of development of diabetes (0 to 6 weeks). 2. There was no change in the TBARS levels of aorta, heart and blood in the control group. A significant (P < 0.05) increase in TBARS levels of aorta, heart and blood was observed in the diabetic group. 3. There were no significant changes in the activities of superoxide dismutase, catalase and glutathione peroxidase in the aorta, heart and blood of control rats at all time intervals. In the diabetic group, there was a significant (P < 0.05) increase in the activity of superoxide dismutase and glutathione peroxidase in aorta from the fourth week onwards while the activity of catalase increased at all time intervals. In the heart of diabetic rats, the activity of total superoxide dismutase and Cu-Zn-superoxide dismutase increased significantly (P < 0.05) from the second week onwards while activity of Mn-superoxide dismutase decreased at the fourth week and increased at the sixth week. The activity of catalase and glutathione peroxidase increased significantly (P < 0.05) at all time intervals. In the blood, the activity of superoxide dismutase and glutathione peroxidase increased from the third week while catalase activity increased from the fourth week. 4. The present findings suggest that oxidative stress starts at early onset of diabetes mellitus and increases progressively.

Chronic Hyperglycemia in Experimental Diabetes mellitus of Short Duration Does Not Contribute to Muscle Capillary Basement Membrane Thickening

The effect of chronic hyperglycemia on the relationship of nonenzymatic glycation and capillary basement membrane thickness in muscle was studied in streptozotocin-induced diabetic rats early in the course of diabetes mellitus. Diabetic animals were placed on either standard (24%) or restricted (8%) protein diet. The animals on 8% protein diet had elevated glycated hemoglobin levels (p less than 0.01) and increased levels of nonenzymatic glycation of basement membrane (p less than 0.01) as compared to insulin-treated diabetic (euglycemic), age-matched control, and streptozotocin-injected nondiabetic animals also on 8% protein diet. In contrast, diabetic animals on restricted (8%) protein diet and those on standard (24%) protein diet showed no statistical differences between them with regards to the above parameters. Moreover, there were no statistical differences among diabetic and control animals on either 8 or 24% protein diet with respect to muscle capillary membrane thickness. Even though the peripheral muscle biopsy study of capillary basement membrane is less invasive than kidney biopsy, the results of this study suggest that neither nonenzymatic glycation nor basement membrane thickness can be utilized as predictors of renal dysfunction during early onset of diabetes mellitus.