Mitochondrial gene mutations in gestational diabetes mellitus

Mitochondrial DNA mutations have been implicated in many diseases including diabetes mellitus. Although gestational diabetes mellitus (GDM) has been suggested to have genetic determinant and to be etiologically indistinct with non-insulin-dependent diabetes mellitus (NIDDM), its association with mitochondrial gene mutations is still unknown. In this study, 137 patients with GDM and 292 non-diabetic pregnant controls were examined for mitochondrial DNA mutations from the nucleotide 3130-4260 encompassing tRNA-Leu gene and adjacent NADH dehydrogenase 1 gene by polymerase chain reaction, single-stranded conformation polymorphism, restriction fragment length polymorphism and DNA sequencing. One heteroplasmic mutation at the position of 3398 (T-C), which changed a highly conserved methionine to threonine in NADH dehydrogenase subunit 1, was identified in 2.9% GDM patients but not in the controls, indicating its association with GDM (P = 0.01). Two novel mutations, a heteroplasmic C3254A and a homoplasmic A3399T, were also found in GDM subjects, the functional meaning of which merits further investigation. G3316A and T3394C mutations implicated in NIDDM, were seen at higher frequencies in patients with GDM than the controls. Our results suggest that mitochondrial DNA mutations may contribute to the development of GDM in some patients.     

线粒体tRNAleu(UUR)基因突变糖尿病

目的 探讨线粒体tRNA^leu(UUR)基因突变糖尿病（MDM）在沈阳地区汉族人中的检出率及其临床表现。方法 应用聚合酶链反应／ApaI酶解法检测100例母亲患有糖尿病（DM）的2型DM患者的tRNA^leu(UUR)基因。结果 100例患者中3例有此基因突变；结合家系调查除认识了本病一般临床表现外，尚发现几种少见表现类型：孪生儿MDM、未被证实为母系遗传的MDM及尚未发病的MDM致病基因携带者。结论 本病在有DM家族史、尤其母亲患有DM的2型DM患者中的检出率为3％；孪生儿MDM更体现了本病呈母系遗传的特点，另有一例未被证实为母系遗传的MDM，需对其进一步研究。     

Mitochondrial dysfunction,insulin resistance,and type 2 diabetes mellitus

Insulin resistance is a characteristic feature of type 2 diabetes mellitus, obesity, and the metabolic syndrome. Increased intracellular fat content in skeletal muscle and liver associated with insulin resistance has led to the hypothesis that a mitochondrial defect in substrate oxidation exists in disorders of insulin resistance. In vivo measurements of metabolic fluxes through the tricarboxylic acid and oxidative phosphorylation with magnetic resonance spectroscopy have demonstrated multiple defects in mitochondrial function in skeletal muscle. A decrease in mitochondrial density and mitochondrial copy number has been reported in insulin-resistant individuals. However, these findings have not been a consistent observation in all studies. Similarly, an intrinsic functional defect in mitochondrial adenosine triphosphate production synthesis has been reported in some but not all studies. This review summarizes evidence that implicates a defect in mitochondrial oxidative phosphorylation and its relationship to insulin resistance in common metabolic diseases characterized by impaired insulin action.     

Mitochondrial bioenergetics is not impaired in nonobese subjects with type 2 diabetes mellitus

Although mitochondrial dysfunction has been well documented in obese people with type 2 diabetes mellitus, its presence or absence in nonobese subjects with type 2 diabetes mellitus has not been well studied so far. The aim of the present study was to assess the status of mitochondrial oxidative phosphorylation in subcutaneous adipose tissue of nonobese type 2 diabetes mellitus subjects in comparison to control, obese nondiabetic, and obese type 2 diabetes mellitus subjects. Mitochondria were isolated from subcutaneous white adipose tissue obtained from the abdominal region of control, obese nondiabetic, nonobese type 2 diabetes mellitus, and obese type 2 diabetes mellitus subjects. The activities of complex I, I to III, II to III, and IV; transmembrane potential; and inorganic phosphate utilization of mitochondria from different groups were measured. Mitochondrial transmembrane potential, inorganic phosphate utilization, and the activities of respiratory chain complexes were significantly reduced in obese nondiabetic and obese type 2 diabetes mellitus patients compared with those in control subjects. No detectable change in mitochondrial functional parameters was observed in case of nonobese type 2 diabetes mellitus subjects compared with control subjects. Furthermore, a significant difference was noticed in mitochondrial phosphate utilization and activities of respiratory complexes, for example, I, I to III, and II to III, between obese type 2 diabetes mellitus subjects and obese nondiabetic subjects. Obesity modulates mitochondrial dysfunction associated with type 2 diabetes mellitus.     

Mitochondrial encephalomyopathy associated with diabetes mellitus, cataract, and corpus callosum atrophy

A 44-year-old woman with mitochondrial encephalomyopathy noticed weakness of the lower extremities at the age of 30 years. She also has type 2 diabetes mellitus, posterior subcapsular cataracts in both eyes, and corpus callosum atrophy. Family history showed that a maternal cousin had a myopathy, 3 maternal aunts had diabetes mellitus, and her mother and 2 maternal aunts had cataracts. External ophthalmoplegia, proximal myopathy, and absent deep tendon reflexes were noted. The mitochondrial DNA 3243 point mutation was negative. Muscle biopsy showed ragged-red fibers, cytochrome c oxidase (COX)-positive fibers, and COX-negative fibers.     

Mitochondrial regulators of fatty acid metabolism reflect metabolic dysfunction in type 2 diabetes mellitus

The delicate homeostatic balance between glucose and fatty acid metabolism in relation to whole-body energy regulation is influenced by mitochondrial function. We determined expression and regulation of mitochondrial enzymes including pyruvate dehydrogenase kinase (PDK) 4, PDK2, carnitine palmitoyltransferase 1b, and malonyl-coenzyme A decarboxylase in skeletal muscle from people with normal glucose tolerance (NGT) or type 2 diabetes mellitus (T2DM). Vastus lateralis biopsies were obtained from NGT (n = 79) or T2DM (n = 33) men and women matched for age and body mass index. A subset of participants participated in a 4-month lifestyle intervention program consisting of an unsupervised walking exercise. Muscle biopsies were analyzed for expression and DNA methylation status. Primary myotubes were derived from biopsies obtained from NGT individuals for metabolic studies. Cultured skeletal muscle was exposed to agents mimicking exercise activation for messenger RNA (mRNA) expression analysis. The mRNA expression of PDK4, PDK2, and malonyl-coenzyme A decarboxylase was increased in skeletal muscle from T2DM patients. Methylation of the PDK4 promoter was reduced in T2DM and inversely correlated with PDK4 expression. Moreover, PDK4 expression was positively correlated with body mass index, blood glucose, insulin, C peptide, and hemoglobin A(1c). A lifestyle intervention program resulted in increased PDK4 mRNA expression in NGT individuals, but not in those with T2DM. Exposure to caffeine or palmitate increased PDK4 mRNA in a cultured skeletal muscle system. Our findings reveal that skeletal muscle expression of PDK4 and related genes regulating mitochondrial function reflects alterations in substrate utilization and clinical features associated with T2DM. Furthermore, hypomethylation of the PDK4 promoter in T2DM coincided with an impaired response of PDK4 mRNA after exercise.     

Mitochondrial DNA mutation at np 3243 in a family with maternally inherited diabetes mellitus

Mitochondrial DNA (mtDNA) gene defects may play a role in the development of maternally inherited diabetes mellitus and deafness (MIDD). A family from Southern Italy who showed maternal transmission of type 2 diabetes mellitus with three individuals affected is described. A 10.4 kb deletion and mutations at nucleotide positions (np) 3243, 7445 and 11778 in the mtDNA of six relatives were sought. The mitochondrial np 3243 mutation of the tRNA Leu (UUR) gene was identified in a boy affected by optic atrophy and mental retardation, as well as in his diabetic mother. No other mutations or deletions were found. Our study points out the variable phenotypic expression of the np 3243 mtDNA mutation. This may suggest the presence of other mitochondrial or nuclear mutations required to modulate the phenotype. A clinical and metabolic follow-up of all family members was necessary to understand the role of the np 3243 mutation, especially in one child affected by optic atrophy and mental retardation. Further studies will be aimed at investigating the prevalence of mutations and deletions of mtDNA in type 2 diabetes mellitus. Received: 20 November 1998 / Accepted in revised form: 20 July 1999     

Mitochondrial metabolism and diabetes

The oversupply of calories and sedentary lifestyle has resulted in a rapid increase of diabetes prevalence worldwide. During the past two decades, lines of evidence suggest that mitochondrial dysfunction plays a key role in the pathophysiology of diabetes. Mitochondria are vital to most of the eukaryotic cells as they provide energy in the form of adenosine triphosphate by oxidative phosphorylation. In addition, mitochondrial function is an integral part of glucose‐stimulated insulin secretion in pancreatic β‐cells. In the present article, we will briefly review the major functions of mitochondria in regard to energy metabolism, and discuss the genetic and environmental factors causing mitochondrial dysfunction in diabetes. In addition, the pathophysiological role of mitochondrial dysfunction in insulin resistance and β‐cell dysfunction are discussed. We argue that mitochondrial dysfunction could be the central defect causing the abnormal glucose metabolism in the diabetic state. A deeper understanding of the role of mitochondria in diabetes will provide us with novel insights in the pathophysiology of diabetes. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00047.x, 2010)     

Post-transplantation diabetes mellitus

Post-transplantation diabetes mellitus (PTDM) is defined as sustained hyperglycemia developing in any patient without history of diabetes before transplantation, that meets the current diagnostic criteria by the American Diabetes Association or the World Health Organization. Several risk factors have been identified: age, nonwhite ethnicity, and glucocorticoid therapy for rejection and chronic immunosuppression with cyclosporine and especially tacrolimus. The pathophysiology of this condition resembles that of type 2 diabetes mellitus: pretransplantation end-stage liver/renal and heart disease are insulin-resistant states, and after transplantation, glucocorticoids induce further peripheral insulin insensitivity. The "second hit" appears to be an acquired (yet reversible) insulin secretion defect resulting from the calcineurin inhibitors cyclosporine and tacrolimus. An international panel of experts has recently published the proceeding of a Consensus Conference proposing strategies for the screening, prevention and management of PTDM. Future directions include pre- and post-transplantation glucose load testing for high-risk individuals and pharmacological agents to decrease insulin resistance and to preserve beta-cell function.     

胰源性糖尿病

胰源性糖尿病是由于胰腺外分泌疾病导致的糖尿病,主要病因为慢性胰腺炎和胰腺癌。目前尚无肯定的诊断标准,容易被忽视和漏诊。胰源性糖尿病患者血糖波动大,胰岛素需要量小,不容易出现糖尿病酮症酸中毒,主要的治疗药物为胰岛素,部分早期患者可使用二甲双胍。     

Gestational diabetes mellitus

Any degree of carbohydrate intolerance which develops for the first time during pregnancy is defined as gestational diabetes mellitus (GDM). GDM is often discovered late, in more than half the cases only during complications associated with pregnancy. Early diagnosis of GDM and early correct therapy of GDM leads to reduction of complications associated with pregnancy, delivery and the perinatal period of the infant. As in our country unequivocal rules for detection of gestational diabetes are still lacking. We feel that introduction of correct routine screening will contribute to the earlier diagnosis of GDM in all women and thus also to appropriate therapy of gestational diabetes.