Vesicular autoantigens of Type 1 diabetes

Type 1 diabetes, also referred to as insulin-dependent diabetes mellitus (IDDM), is an autoimmune disorder resulting from the destruction of pancreatic β-cells and insulin deficiency. In the last 10 years significant progress has been made in this field, primarily because of the identification of predisposing genes, the extensive investigation of animal models, and the characterization of major autoantigens. This review draws attention to how the study of β-cell autoantigens may contribute insight into the pathogenesis of IDDM and provides an update on the cell biology of glutamic acid decarboxylase (GAD) and islet cell autoantigen 512, two major targets of autoimmunity in Type 1 diabetes on which I have focused my efforts. For reasons of space I have mostly considered here studies on GAD which have been published since 1994. © 1998 John Wiley & Sons, Ltd.     

Genetics and pathophysiology of neonatal diabetes mellitus

Neonatal diabetes mellitus (NDM) is the term commonly used to describe diabetes with onset before 6 months‐of‐age. It occurs in approximately one out of every 100,000–300,000 live births. Although this term encompasses diabetes of any etiology, it is recognized that NDM diagnosed before 6 months‐of‐age is most often monogenic in nature. Clinically, NDM subgroups include transient (TNDM) and permanent NDM (PNDM), as well as syndromic cases of NDM. TNDM often develops within the first few weeks of life and remits by a few months of age. However, relapse occurs in 50% of cases, typically in adolescence or adulthood. TNDM is most frequently caused by abnormalities in the imprinted region of chromosome 6q24, leading to overexpression of paternally derived genes. Mutations in KCNJ11 and ABCC8, encoding the two subunits of the adenosine triphosphate‐sensitive potassium channel on the β‐cell membrane, can cause TNDM, but more often result in PNDM. NDM as a result of mutations in KCNJ11 and ABCC8 often responds to sulfonylureas, allowing transition from insulin therapy. Mutations in other genes important to β‐cell function and regulation, and in the insulin gene itself, also cause NDM. In 40% of NDM cases, the genetic cause remains unknown. Correctly identifying monogenic NDM has important implications for appropriate treatment, expected disease course and associated conditions, and genetic testing for at‐risk family members. Early recognition of monogenic NDM allows for the implementation of appropriate therapy, leading to improved outcomes and potential societal cost savings. (J Diabetes Invest, doi:10.1111/j.2040‐1124.2011.00106.x, 2011)     

Aetiology of type 1 diabetes: Physiological growth in children affects disease progression

The prevailing view is that type 1 diabetes (T1D) develops as a consequence of a severe decline in β‐cell mass resulting from T‐cell‐mediated autoimmunity; however, progression from islet autoantibody seroconversion to overt diabetes and finally to total loss of C‐peptide production occurs in most affected individuals only slowly over many years or even decades. This slow disease progression should be viewed in relation to the total β‐cell mass of only 0.2 to 1.5 g in adults without diabetes. Focal lesions of acute pancreatitis with accumulation of leukocytes, often located around the ducts, are frequently observed in people with recent‐onset T1D, and most patients display extensive periductal fibrosis, the end stage of inflammation. An injurious inflammatory adverse event, occurring within the periductal area, may have negative implications for islet neogenesis, dependent on stem cells residing within or adjacent to the ductal epithelium. This could in part prevent the 30‐fold increase in β‐cell mass that would normally occur during the first 20 years of life. This increase occurs in order to maintain glucose metabolism during the physiological increases in insulin production that are required to balance the 20‐fold increase in body weight during childhood and increased insulin resistance during puberty. Failure to expand β‐cell mass during childhood would lead to clinically overt T1D and could help to explain the apparently more aggressive form of T1D occurring in growing children when compared with that observed in affected adults.     

Autoantibodies associated with presymptomatic insulin-dependent diabetes mellitus in women

Presymptomatic autoantibody markers of insulin-dependent (Type 1) diabetes mellitus (IDDM) are less well characterized in adults than in children. We quantitated anti-GAD, anti-ICA512 and ICA by titration to endpoint and compared frequencies and levels in 139 Finnish women from whom 390 serum samples had been archived during antecedent pregnancies for 10 years before and up to 1 year after diagnosis of diabetes. Also, we compared the autoantibody status in adults with IDDM with that of children with newly diagnosed IDDM. Of the 35 women seropositive for 1 or more autoantibodies, 77 % developed IDDM, 11 % non-insulin-dependent (Type 2) diabetes mellitus (NIDDM), 9 % gestational diabetes mellitus requiring insulin (GDM-ins) and 3 % GDM controlled by diet. The frequency of antibodies during the 10-year presymptomatic period was 83 % for anti-glutamic acid decarboxylase (GAD), 52 % for anti-ICA512 and 41 % for islet cell antibodies (ICA) for those who developed IDDM, 25 %, 17 %, and 0 % for NIDDM, 12 %, 4 %, and 8 % for GDM-ins and 1 %, 0 %, and 1 % for GDM-diet. Anti-GAD was found most consistently in early samples; 13 of 15 with a single autoantibody at their first test had anti-GAD. Among those who developed IDDM, the frequency of anti-GAD was constant, anti-ICA512 increased threefold, and ICA increased slightly before diagnosis. Levels of the autoantibodies varied between subjects, but were relatively stable in individual subjects. Comparison of tests on the women, and children after diagnosis of IDDM, showed the frequencies and levels to be the same for anti-GAD but lower for anti-ICA512 and ICA in adults. Our observations show in women the long latency of seropositivity before overt IDDM, the predominance of anti-GAD among these three serological markers, and the presence of these markers in NIDDM presumably representing a NIDDM phase of autoimmune insulitis. © 1997 by John Wiley & Sons, Ltd.     

Emerging concepts in the pathogenesis of diabetes in fibrocalculous pancreatic diabetes

Fibrocalcific pancreatic diabetes (FCPD) is a rare form of diabetes affecting people in the tropics and presenting with unique clinical and radiological features. The onset of diabetes usually follows the first few episodes of abdominal pain and develops by the second or third decade of life. Endocrine and exocrine pancreatic insufficiency, brittle glycemic control, and insulin‐requiring, ketosis‐resistant diabetes are the novel characteristics of FCPD. The etiopathogenetic mechanisms leading to FCPD remain unknown. Although defects in insulin secretion are the major contributors, growing evidence towards a possible role for insulin resistance and body composition abnormalities have added a new dimension to the disease pathogenesis. Deciphering the key pathogenetic mechanisms may have a profound effect on therapeutic strategies in future studies on FCPD.     

Islet cell antibodies and diabetes mellitus in Pima Indians

Summary Pancreatic islet cell antibodies and 12 other autoantibodies were measured at the time of diabetes diagnosis in 46 Pima Indians, aged 17–47 years, and in 46 age-sex matched non-diabetic controls. Islet cell antibodies were found in only two diabetics, aged 20 and 25, compared with none of 46 controls. Neither of the subjects with islet cell antibodies had other autoantibodies. At least one type of autoantibody was found in 14 (30%) of the diabetics and in 14 controls, but none was significantly associated] with diabetes. This study indicates that diabetes in the Pima Indians, even those with an onset below 25 years of age, is almost entirely of type II, in that the disease is not associated with islet cell antibodies, ketoacidosis, or insulin dependence.     

Reappraisal of metallothionein: Clinical implications for patients with diabetes mellitus

Reactive oxygen and nitrogen species (ROS and RNS, respectively) are byproducts of cellular physiological processes of the metabolism of intermediary nutrients. Although physiological defense mechanisms readily convert these species into water or urea, an improper balance between their production and removal leads to oxidative stress (OS), which is harmful to cellular components. This OS may result in uncontrolled growth or, ultimately, cell death. In addition, ROS and RNS are closely related to the development of diabetes and its complications. Therefore, numerous researchers have proposed the development of strategies for the removal of ROS/RNS to prevent or treat diabetes and its complications. Some molecules that are synthesized in the body or obtained from food participate in the removal and neutralization of ROS and RNS. Metallothionein, a cysteine‐rich protein, is a metal‐binding protein that has a wide range of functions in cellular homeostasis and immunity. Metallothionein can be induced by a variety of conditions, including zinc supplementation, and plays a crucial role in mediating anti‐OS, anti‐apoptotic, detoxification, and anti‐inflammatory effects. Metallothionein can modulate various stress‐induced signaling pathways (mitogen‐activated protein kinase, Wnt, nuclear factor‐κB, phosphatidylinositol 3‐kinase, sirtuin 1/AMP‐activated protein kinase and fibroblast growth factor 21) to alleviate diabetes and diabetic complications. However, a deeper understanding of the functional, biochemical, and molecular characteristics of metallothionein is needed to bring about new opportunities for OS therapy. This review focuses on newly proposed functions of a metallothionein and their implications relevant to diabetes and its complications.     

Changing environment of hyperglycemia in pregnancy: Gestational diabetes and diabetes mellitus in pregnancy

The diagnosis and treatment of gestational diabetes mellitus (GDM) have been in a state of flux since the World Health Organization accepted and endorsed the International Diabetes and Pregnancy Study Group's diagnostic pathway and criteria in 2013. These new diagnostic criteria identify an increasing number of women at risk of hyperglycemia in pregnancy (HGiP). Maternal hyperglycemia represents a significant risk to the mother and fetus, in both the short and long term. Controversially, metformin use for the treatment of GDM is increasing in Australia. This article identifies the multiple and varied presentations of HGiP, of which GDM is the most commonly encountered. The degree of maternal hyperglycemia experienced affects the outcomes for both the mother and neonate, and specific diagnosis determines the appropriate treatment for the pregnancy. Given the increasing incidence of women with dysglycemia and those developing HGiP, this is an important area for research and clinical attention for all health professionals.     

Ocular autofluorescence in diabetes mellitus. A review

Diabetes mellitus is a metabolic disease with a considerable impact on healthcare owing to its increased prevalence and high mortality rate. Structural, morphological, and physiological changes in each of the ocular components have been described in detail. Autofluorescence has been described as a good indicator of metabolic activity. The aim of the present review is to provide an overview of ocular endogenous fluorophores in the cornea, the crystalline lens, and the retinal pigment epithelium, the effects of diabetes mellitus and therefore the potential of autofluorescence assessment for screening and monitoring changes in diabetic patients.     

Islet cell antibodies and other markers of autoimmunity and diabetes mellitus in Nauruans

Summary Among the population of Nauru there is a high prevalence of diabetes with onset in early adult life. To ascertain whether autoimmunity to islet cell antigens contributes to this diabetes, a population survey of serum autoantibodies was performed. Subjects were grouped into euglycaemic control subjects, those with impaired glucose tolerance, and those with diabetes subdivided according to duration of disease. No subject was positive by immunofluorescence for islet cell autoantibodies. Various other autoantibodies to nuclear, thyroid and gastric autoantigens were detectable, at comparable frequencies in the three groups. This population study on Nauruan subjects selected to include those in the early phases of disease negates a contribution from islet cell autoimmunity, and thus supports the concept that the disease is the Type 2 (non-insulin-dependent) type.     

Prevention of insulin-dependent diabetes mellitus 1998

Recent advances in the understanding of the pathogenesis of insulin-dependent diabetes mellitus (IDDM) have led to the first trials of disease prevention in susceptible individuals. Two main trials (nicotinamide and insulin) are now running but first results will not be available before the turn of the century. Pilot trials using different approaches, most of them based on the induction of immunotolerance, are also under way and should offer new insight for establishing larger multicentre studies including attempts aimed at primary prevention by removal of diabetogenic components in cow’s milk. The field is moving fast and it is expected that intervention for IDDM prevention will be offered to an increasing number of individuals found at risk of developing the disease. © 1998 John Wiley & Sons, Ltd.