Genetik des Diabetes mellitus Typ 2 und verwandter Diabetesformen

Type 2 diabetes mellitus has reached epidemic proportions worldwide and is also becoming increasingly important in pediatrics. Family studies and twin studies have shown that the genetic predisposition has an important impact on the development of type 2 diabetes. Genome-wide linkage studies and association studies have identified various candidate genes that are thought to be involved in the development of type 2 diabetes. Polymorphisms in the PPARγ gene, the KCNJ11 gene, and the insulin receptor substrate 1 gene and others are associated with an elevated risk of development of type 2 diabetes. In addition, these studies also suggest that the genetic predisposition to type 2 diabetes differs in different populations. Elucidation of the molecular basis of monogenetic forms of diabetes associated with insulin resistance or disturbed insulin secretion has also added to our understanding of the pathogenesis of type 2 diabetes.     

Sulfonylurea challenge test in subjects diagnosed with type 1 diabetes mellitus

Background: Patients with early onset diabetes because of defects in glucose‐stimulated insulin secretion (GSIS) may respond better to sulfonylureas than insulin treatment. Such patients include those with monogenic disorders, who can be differentiated from autoimmune type 1 diabetes mellitus (T1DM) by genetic testing. Genetic testing is expensive and unknown defects in GSIS would not be diagnosed. Aims: We propose a sulfonylurea challenge test to identify patients who have been clinically diagnosed with T1DM, but those who maintain a preferentially sulfonylurea‐responsive insulin secretion. Materials & Methods: A total of 3 healthy controls, 2 neonatal diabetes mellitus (NDM) subjects, 3 antibody‐positive (Ab+T1DM), and 12 antibody‐negative (Ab?T1DM) subjects with type 1 diabetes, were given an intravenous bolus of glucose followed by an oral dose of glipizide. Results: Healthy controls showed a robust C‐peptide increase after both glucose and glipizide, but NDM subjects showed a large increase in C‐peptide only following glipizide. As expected, 2 of 3 Ab+T1DM, as well as 11 of 12 Ab?T1DM showed no response to either glucose or glipizide. However, 1 Ab?T1DM and 1 Ab+T1DM showed a small C‐peptide response to glucose and a marked positive response to glipizide, suggesting defects in GSIS rather than typical autoimmune diabetes. Discussion: These data demonstrate the feasibility of the sulfonylurea challenge test, and suggest that responder individuals may be identified. Conclusions: We propose that this sulfonylurea challenge test should be explored more extensively, as it may prove useful as a clinical and scientific tool.     

Type 2 diabetes in a 5‐year‐old and single center experience of type 2 diabetes in youth under 10

The worrisome rise in pediatric type 2 diabetes (T2DM) is most prevalent among minority ethnic/racial populations. Typically, T2DM occurs during puberty in high risk obese adolescents with evidence of insulin resistance. Screening for T2DM in obese youth can be a daunting task for pediatricians and differentiating between pediatric T1DM and T2DM in obese youth can be challenging for pediatric endocrinologists. There is very limited data regarding the prevalence of T2DM among youth < 10 years of age. Here we present the case of a 5‐year‐old Hispanic male diagnosed with T2DM after referral by his pediatrician for abnormal weight gain, acanthosis nigricans and an elevated HbgA1c. He subsequently became symptomatic for diabetes with confirmed hyperglycemia and HbgA1c of 9.7% (83 mmol/mol) at the time of formal diagnosis. Type 1 diabetes autoantibodies (GAD65, Islet, and ZincT8) and monogenic diabetes genetic tests were negative. Due to elevated liver enzymes and baseline HbgA1c, he received basal insulin as his initial therapy. In this paper, we will discuss this case and present an IRB approved retrospective review of the characteristics of the 20 T2DM patients <10 years of age identified to date in our pediatric diabetes center. This review highlights that while uncommon, the diagnosis of T2DM merits consideration even in prepubertal children. This is especially true when working with a high risk population, such as our Hispanic South Texas youth.     

Prediction and prevention of type 1 diabetes: update on success of prediction and struggles at prevention

Type 1 diabetes mellitus (T1DM) is the archetypal example of a T cell‐mediated autoimmune disease characterized by selective destruction of pancreatic β cells. The pathogenic equation for T1DM presents a complex interrelation of genetic and environmental factors, most of which have yet to be identified. On the basis of observed familial aggregation of T1DM, it is certain that there is a decided heritable genetic susceptibility for developing T1DM. The well‐known association of T1DM with certain human histocompatibility leukocyte antigen (HLA) alleles of the major histocompatibility complex (MHC) was a major step toward understanding the role of inheritance in T1DM. Type 1 diabetes is a polygenic disease with a small number of genes having large effects (e.g., HLA) and a large number of genes having small effects. Risk of T1DM progression is conferred by specific HLA DR/DQ alleles [e.g., DRB1*03‐DQB1*0201 (DR3/DQ2) or DRB1*04‐DQB1*0302 (DR4/DQ8)]. In addition, the HLA allele DQB1*0602 is associated with dominant protection from T1DM in multiple populations. A concordance rate lower than 100% between monozygotic twins indicates a potential involvement of environmental factors on disease development. The detection of at least two islet autoantibodies in the blood is virtually pre‐diagnostic for T1DM. The majority of children who carry these biomarkers, regardless of whether they have an a priori family history of the disease, will develop insulin‐requiring diabetes. Facilitating pre‐diagnosis is the timing of seroconversion which is most pronounced in the first 2 yr of life. Unfortunately the significant progress in improving prediction of T1DM has not yet been paralleled by safe and efficacious intervention strategies aimed at preventing the disease. Herein we summarize the chequered history of prediction and prevention of T1DM, describing successes and failures alike, and thereafter examine future trends in the exciting, partially explored field of T1DM prevention.     

Genetic interaction among three genomic regions creates distinct contributions to early- and late-onset type 1 diabetes mellitus

There are two peaks in the distribution of the age of onset of type 1 diabetes mellitus (T1DM)--the first in early childhood and the second at the time of puberty. Although T1DM results from the interaction of genetic and non-genetic factors, it has not been established which factors contribute to the bimodal distribution. The genetic component of T1DM is in large part related to genes from the human leukocyte antigen (HLA) complex (IDDM1); however, loci from the variable nucleotide tandem repeat (VNTR) region of the insulin (INS) gene (IDDM2) and more recently, the cytotoxic T-lymphocyte-associated protein-4 region (CTLA4, IDDM12) have also been implicated. Therefore, we examined the potential interaction between these loci through the influence of the age of onset of T1DM in diabetic and control Caucasian individuals. We discovered that younger individuals with HLA-DRB1*0301/DRB1*04 and INS I/I genotypes exhibited increased susceptibility to T1DM, whereas the interaction of INS I/I and CTLA4 G/G genotypes was more common in older children with T1DM. Combining the age of onset of T1DM with specific genotypes may operate to produce a single disease through different underlying causes.     

Pathophysiologie und Spätfolgen des Diabetes mellitus Typ 2

Type 2 diabetes mellitus (T2DM) is characterised by the combination of insulin resistance and insulin secretion deficiency, which intensify each other. T2DM is caused by genetic predisposition, physical inactivity, and obesity. Adipose tissue produces multiple adipocytokines, which are closely related to insulin resistance. A vicious circle is set up with the insulin resistance in adipose tissue, muscle and liver together with the resultant decreased glycolysis and glycogen synthesis and increased gluconeogenesis intensifying the insulin resistance. Consequences of the resulting hyperglycemia are microvascular complications such as retinopathy and damage to kidneys and the nervous system. Dyslipidaemia and hypertension are frequently associated with T2DM, but macrovascular complications must also be expected.     

Genetics and type 2 diabetes in youth

Abstract:  The rapid increase in the population prevalence of type 2 diabetes mellitus (T2DM) in youth can only be explained by changes in lifestyle. However, even when most members of a population have changed their lifestyle, only a minority of children develop diabetes, and genetic factors are important in determining which children are affected. Support for the role of genetic factors comes from epidemiological evidence that diabetes in youth is most common in high diabetes prevalence racial groups, in subjects with a strong family history, and in girls. Defining the genes predisposing to T2DM is extremely difficult as there are multiple genes involved each contributing only a small amount and lifestyle factors play a large role. Defining the molecular genetics of T2DM in youth is even harder because in addition to the low number of subjects, there is also the ethnic heterogeneity of the subjects and the lack of robust diagnostic criteria. Recently, there has been considerable progress in defining the predisposing genes for adults with T2DM using thousands of cases and controls and a collaborative genome-wide approach. Similar numbers will be needed to assess if the genes found in adults also predispose to T2DM of youth and this will require large multi-center studies. Progress to date in the molecular genetics of T2DM in youth is limited to one population, the Oji-Cree Native Canadians, where the private variant – G319S – a variant of HNF1A strongly predisposes to diabetes in children as well as in adults.     

Metabolic differences between Caucasian and African-American children and the relationship to type 2 diabetes mellitus

Type 2 diabetes mellitus (DM) has historically been considered an adult disease. However, the incidence of type 2 DM has increased dramatically in pediatric populations in recent years. This increase parallels the recent rise in childhood obesity and has been greatest among minority adolescents. Differences between African-American and white American youths are discussed, including risk factor differences that may help to account for the overwhelming number of African-American children with type 2 DM as compared with white children. African-American youths have higher rates of insulinemia, obesity, family history, and acanthosis nigricans than their white counterparts. In addition, despite similar declines in insulin action during puberty, there is no compensatory increase in insulin secretion in African-American children, contrary to the observation in white children. These differences are likely to have a genetic basis modulated by environmental and lifestyle influences. Treatment of type 2 DM should focus on identifying individuals at risk and instituting lifestyle changes to reduce the risk and stem the development of DM.     

Epilepsy in children with type 1 diabetes mellitus: Pathophysiological basis and clinical hallmarks

We provide an overview on the current knowledge about the association between epilepsy and type 1 diabetes mellitus (T1DM). People with T1DM have a 2–6-fold higher risk of epilepsy than the general population. The onset of T1DM anticipates the onset of epilepsy by a mean period between 1,5 and 2,8 years. These two disorders share four potential distinct pathogenic factors: a) genetic predisposition; b) factors involved in autoimmune responses (i.e. anti-glutamic acid decarboxylase antibodies-GADAbs); c) effects of hypo/hyperglycaemia; d) cerebrovascular damages resulting in ischaemic processes.Seizures semiology prominently includes focal (up to patterns of epilepsia partialis continua) or secondarily generalized seizures but also reflex seizures and various forms of generalized seizures. EEG abnormalities are more common in people with an inappropriate metabolic control with a prominent involvement of fronto-temporal regions.Epilepsy management does not differ between patients with and without diabetes and insulin, nutritional recommendations and physical activity may also produce significant benefits on seizures control. Possible therapeutic alternatives in selected cases include immunosuppressive drugs (in patients with GADAbs) and ketogenic diet.     

Childhood obesity and type 2 diabetes mellitus

Until recently, the majority of cases of diabetes mellitus among children and adolescents were immune-mediated type 1a diabetes. Obesity has led to a dramatic increase in the incidence of type 2 diabetes (T2DM) among children and adolescents over the past 2 decades. Obesity is strongly associated with insulin resistance, which, when coupled with relative insulin deficiency, leads to the development of overt T2DM. Children and adolescents with T2DM may experience the microvascular and macrovascular complications of this disease at younger ages than individuals who develop diabetes in adulthood, including atherosclerotic cardiovascular disease, stroke, myocardial infarction, and sudden death; renal insufficiency and chronic renal failure; limb-threatening neuropathy and vasculopathy; and retinopathy leading to blindness. Health care professionals are advised to perform the appropriate screening in children at risk for T2DM, diagnose the condition as early as possible, and provide rigorous management of the disease.     

胰岛β细胞再生与转化研究进展

1型糖尿病(type 1 diabetes mellitus,T1DM)是一种以胰岛β细胞进行性损伤、胰岛素分泌绝对不足为基础的器官特异性自身免疫性疾病,终生皮下注射胰岛素仍为目前主要的治疗手段.但该治疗方法给患者带来巨大痛苦,且不能改善远期预后.随着现代医学的发展,医生可利用基因技术等综合手段,实现胰岛β细胞的再生与转化,尽可能保护T1DM患者残存胰岛β细胞功能,为防止T1DM急慢性并发症的发生提供了新的思路.目前有关胰岛β细胞重建的研究主要集中于胰岛移植、干细胞移植、免疫调节剂的应用等,但多因自身局限,不能满足临床需求.胰岛δ细胞原位转化为胰岛素分泌细胞的研究,因其独特的优势,成为目前的研究热点.该文将对胰岛δ细胞原位转化的技术手段、影响因素、可能机制等方面进行综述.     

Impaired beta-cell and alpha-cell function in African-American children with type 2 diabetes mellitus--"Flatbush diabetes"

The incidence of type 2 diabetes mellitus (T2DM) in children and adolescents has substantially increased over the past decade. This is attributed to obesity, insulin resistance and deficient beta-cell function. In children a pubertal increase in insulin resistance and an inability to mount an adequate beta-cell insulin response results in hyperglycemia. Adults with T2DM have a diminished first phase response to intravenous glucose and a delayed early insulin response to oral glucose. Long-term studies show progressive loss of beta-cell function in T2DM in adults; however, such long-term studies are not available in children. To characterize beta- and alpha-cell function in African-American adolescents with established T2DM, we used mixed meal, intravenous glucagon and oral glucose tolerance testing and compared them to obese non-diabetic controls. T2DM was defined as fasting C-peptide >0.232 nmol/l and absent autoimmune markers. BETA-CELL FUNCTION: Meal testing in 24 children and adolescents with T2DM, mean age 14 years, BMI 30 kg/m2, Tanner stage II-V, HbA1c 8.9%, were compared with BMI- and age-matched controls. Forty percent presented with DKA. Half were treated with insulin and half with diet/oral anti-diabetic agents. Although absolute C-peptide response in both groups was similar, the incremental rise in C-peptide relative to plasma glucose in the patients with T2DM compared to controls was 40% and 35% lower 30 and 60 min after the meal, p <0.007 and p <0.026. Glucagon testing in 20 pediatric patients with T2DM compared with 15 matched controls showed significantly lower 6 min stimulated C-peptide relative to the ambient plasma glucose in patients with T2DM compared to controls (0.039 +/- 0.026 vs 0.062 +/- 0.033, p <0.05). The clinical utility is that 78% of patients with a 6 min C-peptide <1.4 nmol required insulin, while 81% of those >1.4 nmol required oral anti-diabetic agents, p <0.0001. Furthermore, the duration of T2DM up to 5 years after diagnosis was associated with lower fasting and glucagon-stimulated C-peptide levels, implying worsening beta-cell function over time, even in children and adolescents. ALPHA-CELL FUNCTION: During meal testing, children and adolescents with T2DM had less suppression of plasma glucagon than non-diabetic controls; this was more severe with longer duration of T2DM and poorer glycemic control. BETA-CELL RECOVERY: In African-American and Hispanic adults, intensive treatment of blood glucose may achieve beta-cell recovery with 35-40% of newly diagnosed patients going into remission after 6 months treatment. They remain off anti-diabetic pharmacological agents in remission for a median of over 3 years with normal HbA1c levels. We hypothesize this to be due to removal of a critical component of glucose or lipotoxicity at the level of the beta-cell and/or peripheral tissue. Four of 20 African-American children presenting with mean glucose 650 mg/dl maintained normal HbA1c levels on small doses of metformin after initial treatment with multiple insulin injections with or without metformin. This suggests a marked recovery of beta-cell function, similar to that in adults. SUMMARY: T2DM in children, as in adults, is characterized by insulin deficiency relative to insulin resistance. Plasma C-peptide levels may be clinically useful in guiding therapeutic choices, since patients with lower levels required insulin treatment; beta-cell function is also diminished with longer duration of T2DM. The possibility exists that in children, as in adults, intensive glycemic regulation may allow for beta-cell recovery and preservation. Thus, optimum beta- and alpha-cell function are central to the prevention of DM and maintenance of good glycemic control in African-American and Hispanic children and adolescents with T2DM.     

Does obesity cause type 2 diabetes mellitus (T2DM)? Or is it the opposite?

Obesity is believed to be a promoter of type 2 diabetes mellitus (T2DM). Reports indicate that severe obesity in childhood and adolescence increases the risk of T2DM in youth and young adults. T2DM, which is commonly asymptomatic, frequently is not recognized until random blood glucose is measured. Screening blood glucose levels measured in obese individuals are more effective for identifying undiagnosed persons, than screening the general population and therefore introduces a selection bias for discovery. The following commentary will indicate why these observations do not indicate that obesity is the cause of T2DM. Also, it will be shown that the insulin resistance of T2DM occurs primarily in the muscles of lean individuals predisposed to diabetes before they become obese. This insulin resistance is not secondary to, but instead, is the cause of the excessive fat accumulation associated with T2DM. Moreover, this early muscle insulin resistance is the etiology of the hyperlipidemia and excess fat accumulation characteristic of T2DM.     

Diabetes and insulin resistance in pediatric obesity

Over the past 2 decades, the prevalence of obesity and type 2 diabetes mellitus (T2DM) in children and adolescents has risen to epidemic proportions and disproportionately affects racial and ethnic minorities, who are at greater risk. The pathophysiology of T2DM is complex and involves insulin resistance, pancreatic β-cell dysfunction, and visceral adiposity. Current treatments of T2DM are limited to lifestyle intervention, metformin, and insulin therapy; use of these strategies in combination is often most effective. The role of research is to uncover simple biomarkers for insulin sensitivity and optimal and innovative treatment of insulin resistance and T2DM.     

Progressive beta cell failure in type 2 diabetes mellitus of youth

The pathophysiology of type 2 diabetes mellitus (T2DM) involves insulin resistance and insulin deficiency. We report the progression in insulin sensitivity and secretion over a 6-year period in an adolescent with T2DM. This report further demonstrates that the earliest abnormality in youth T2DM is insulin resistance followed by progressive beta-cell failure.     

Population genetics in minority children with type 2 diabetes mellitus

Non-insulin dependent (type 2) diabetes mellitus (DM) is a rapidly emerging health threat in minority populations in the United States, with the African-American, Hispanic, and Native American populations at greatest risk. Clearly, environmental factors play a role in this disorder, but the ethnic predilection suggests a significant genetic component. Type 2 DM is a condition not well understood on a genetic basis. Familial clustering and ethnic variation have been documented. The populations of Africans living in diverse environments provide a unique opportunity to study type 2 DM as the mechanism is becoming more clear.     

Gastric emptying and postprandial glucose excursions in adolescents with type 1 diabetes

Because amylin is co-secreted with insulin from beta cells, patients with type 1 diabetes (T1DM) are deficient in both insulin and amylin. Amylin delays gastric emptying and suppresses glucagon in the postprandial period. Hence, we hypothesized that children with complication-naive T1DM have accelerated gastric emptying in response to a mixed meal because of amylin deficiency. Amylin, glucagon, insulin, glucose, and gastric emptying were measured in seven T1DM and in eight control subjects without diabetes. Subjects with T1DM had markedly elevated glucose concentrations when compared with controls (p < 0.0001). Amylin concentrations as predicted were lower in T1DM compared with those in controls (p < 0.0001). Insulin did not peak in the immediate postprandial period in T1DM when compared with controls (p < 0.0001). Glucagon concentrations did not significantly differ between groups. Interestingly, gastric velocity was delayed in patients with T1DM compared with controls (p < 0.01). In conclusion, subjects with T1DM do have amylin deficiency but this is not associated with accelerated gastric emptying as we had hypothesized but rather with delayed gastric emptying. Factors other than amylin play a role in control of gastric motility in T1DM. Subcutaneous insulin delivery fails to reach adequate concentrations in the postprandial period to curtail peak glucose concentration in T1DM.     

Impaired β‐cell sensitivity to glucose and maximal insulin secretory capacity in adolescents with type 2 diabetes

Elder DA, Woo JG, D’Alessio DA. Impaired β‐cell sensitivity to glucose and maximal insulin secretory capacity in adolescents with type 2 diabetes. Background: Adults with type 2 diabetes mellitus (T2DM) have broad impairments in β‐cell function, including severe attenuation of the first‐phase insulin response to glucose, and reduced β‐cell mass. In adolescents with T2DM, there is some evidence that β‐cell dysfunction may be less severe. Our objective was to determine β‐cell sensitivity to glucose and maximal insulin secretory capacity (AIR_max) in teenagers with T2DM. Methods: Fifteen adolescents with T2DM [11 F/4 M, age 18.4 ± 0.3 yr, body mass index (BMI) 39.8 ± 2.2 kg/m²] and 10 non‐diabetic control subjects (7 F/3 M, age 17.4 ± 0.5 yr, BMI 41.5 ± 2.2 kg/m²) were studied. T2DM subjects had a mean duration of diabetes of 48.8 ± 6.4 months, were treated with conventional therapies, and had good metabolic control [hemoglobin A1c (HbA1c) 6.7 ± 1.2%]. Insulin and C‐peptide were determined before and after a graded glucose infusion and after intravenous arginine at a whole blood glucose level of ≥22 mM. Results: The insulin response to increasing plasma glucose concentrations was blunted in the diabetic compared with control subjects (34.8 ± 11.9 vs. 280.5 ± 57.8 pmol/mmol; p < 0.0001), and AIR_max was also significantly reduced in the diabetic group (1868 ± 330 vs. 4445 ± 606; p = 0.0005). Conclusion: Even adolescents with well‐controlled T2DM have severe impairments of insulin secretion. These data support β‐cell dysfunction as central in the pathogenesis of T2DM in young people, and indicate that these abnormalities can develop over a period of just several years.     

Genetics of type 1 diabetes mellitus

Type 1 Diabetes Mellitus is a complex and polygenic disease due to gene-environment interactions. The role of genetic background of diabetes has been extensively investigated. However, final conclusions have not yet been reached. Family and twin studies have shown that genetic factors are important contributors to the genetic risk of the disease. Although more than 18 diabetes-predisposing genes have been reported to date, only the major histocompatibility complex (HLA) region on chromosome 6p21 (IDDM1) and the insulin gene on chromosome 11p15 (IDDM 2) have been conclusively associated with susceptibility to type 1 diabetes. However, it has been shown recently that cytotoxic lymphocyte antigen 4 (CTLA4) on chromosome 2q33 (IDDM12) and LYP/PTPN22 on chromosome 1p13 also contribute to the genetic risk of T1DM. The article reviews the recent advances in this field. By identifying new loci or reanalyzing the known ones and with the help of more powerful studies, it is possible in the future to be able to shed more light on the complex field of the genetics of type 1 diabetes and to further understand the pathophysiology of the disease, which will allow us eventually to treat or prevent it.