Fast Facts: Type 1 Diabetes in Adults

By R. Zaidi, P. Weston and J. Brake

'Fast Facts: Type 1 Diabetes in Adults' provides a practical overview of this chronic autoimmune condition. Written by and for health professionals working in primary care, this colourful and accessible handbook highlights important practice points that cover: • the identification and management of adults with type 1 diabetes • the prevention and treatment of complications • advances in technology and future treatments An indispensable read for anyone wanting to get up to speed with best practice in primary care. Table of Contents: • Overview • Diagnosis • Management • Hypoglycemia • Education • Special circumstances • Complications • Living with the condition • Technology • Future treatments

• Language: English
• Publisher: S. Karger
• Release date: Oct 7, 2021
• ISBN: 9783318069167

Book preview

Introduction

Type 1 diabetes is a chronic autoimmune condition characterized by insulin deficiency and resultant hyperglycemia that is distinct from the more prevalent type 2 diabetes. The nomenclature has evolved from the early 20th century use of ‘insulin-sensitive diabetes mellitus’, through ‘juvenile-onset’ and ‘insulin-dependent diabetes mellitus’ in the 1950s, to the adoption of the ‘type 1 diabetes’ terminology in the late 1990s. Over the last three decades, our knowledge of type 1 diabetes has increased rapidly because of better understanding of genetics, epidemiology and β cell dysfunction. Major developments in diagnostic methods, monitoring tools and insulin delivery options have improved outcomes for people living with the condition; however, wide gaps still exist in our understanding of the condition and ability to standardize care across levels of healthcare.

In this resource, we cover the key areas of type 1 diabetes in adults as seen through the lens of multidisciplinary specialist medical professionals and, most importantly, an expert member of a family living with and around the condition. There is particular emphasis on recent developments in insulin pharmacokinetics, monitoring and therapeutic technology, and models of education.

This handbook will be ideal for all care providers across the healthcare spectrum and adults living with type 1 diabetes looking to raise awareness and broaden their understanding of this omnipresent condition, therapeutic modalities and potential complications. Through this book, we hope to improve advocacy and care, and positively impact healthcare outcomes and the quality of life of people living with type 1 diabetes.

Acknowledgment. The authors thank Dr Joan St John, London North West University Healthcare NHS Trust and North West London Diabetes Transformation programme, for helpful comments on the manuscript.

Normal physiology of insulin synthesis and action

Insulin is synthesized in and secreted exclusively from β cells within the islets of Langerhans in the pancreas.¹ Synthesis begins with a larger precursor, preproinsulin, which is cleaved by proteases into proinsulin. This is further cleaved by enzymes into insulin and connecting peptide (C-peptide) (Figure 1.1). The active insulin molecule consists of two polypeptide chains linked by disulphide bridges; the A chain has 21 amino acids and the B chain 30 amino acids.

Glucose is the main stimulator of insulin release, which occurs in a biphasic pattern: the first ‘acute phase’ lasts a few minutes, followed by a sustained ‘second phase’. Glucose metabolism in the β cell is governed by glucokinase activity that, in turn, determines the glucose–insulin dose–response curve. Half-maximal stimulation of insulin release occurs at a glucose level of 8 mmol/L (144 mg/dL) with no secretion at levels of 5 mmol/L (90 mg/dL) and below.

Glucose transporters. Insulin binds to a glycoprotein cell surface receptor, initiating the phosphorylation of amino acids by the enzyme tyrosine kinase. Glucose molecules are transported into cells via specialized proteins, the glucose transporters (GLUTs). With the exception of GLUT-4, transport by GLUTs is non-insulin-mediated in the muscles and adipose tissue.

Blood glucose levels are tightly controlled in people without diabetes at around 5 mmol/L (90 mg/dL) by the balance of glucose entry into the circulation from the liver and intestinal absorption, and peripheral uptake by muscle and adipose tissue. Insulin is secreted at a low, ‘basal’ level in the non-fed/fasted state and 80% of glucose consumption is by the brain in a non-insulin-dependent manner.

At mealtimes, insulin secretion is stimulated to increase peripheral uptake of glucose, and liver glycogen breakdown (glycogenolysis) and the formation of ‘new’ glucose from substrates such as glycerol, lactate and amino acids (gluconeogenesis) is reduced (Figure 1.2). Insulin also directly reduces lipolysis and promotes lipogenesis in white adipose tissue.

Figure 1.1 Insulin biosynthesis showing the cleavage of proinsulin into insulin and C-peptide. Letters denote the different peptide chains. Adapted from Bilous and Donnelly 2010.¹

Evolution of type 1 diabetes

Insulin deficiency is the hallmark of type 1 diabetes.² Type 1a is caused by immune destruction of β cells of the islets of Langerhans by autoantibodies. Type 1b is a rare form of idiopathic insulin deficiency that lacks evidence of an autoimmune etiology.

The most widely accepted hypothesis for the evolution of type 1 diabetes describes genetically susceptible individuals being exposed to putative environmental factors at a certain point in their lives (Figure 1.3). These trigger a destructive T cell-mediated autoimmune process, resulting in diffuse lymphocytic infiltration of the islets, known as insulitis, and β cell loss over a period of time. This results in the loss of the first phase of insulin response to intravenous glucose, insulin deficiency and, eventually, overt clinical diabetes because of severe abnormalities in the metabolism of carbohydrates, fat and protein. Although symptoms of hyperglycemia appear when approximately 90% of the β cells are destroyed, there is evidence that residual insulin production can last for months and, in some cases, years after diagnosis.

Figure 1.2 Profiles of insulin and blood glucose concentrations with time of the day in individuals without diabetes. Mealtimes are represented by the arrows.

Figure 1.3 Stages in the development of type 1 diabetes.

Genetic factors

Type 1 diabetes is a complex genetic trait. Multiple inherited genetic factors influence both susceptibility and resistance to the condition. Familial clustering of type 1 diabetes is suggested by an average risk of 6% in siblings, compared with 0.4% in the general population.² The concordance for type 1 diabetes is approximately 30–50% for monozygotic or identical twins (who share 100% of their genes). Nevertheless, a family history of type 1 diabetes is more likely to be absent than present in index cases.

Many studies have evaluated candidate genes for disease association, leading to the identification of two chromosomal regions with consistent and significant association with type 1 diabetes. Other susceptibility loci have been identified in certain groups of people with type 1 diabetes.

The HLA region is a cluster of genes located within the major histocompatibility complex (MHC) on chromosome 6p21. Of these genes, it is estimated that the HLA region (designated the major locus of type 1 diabetes IDDM1 [also known as HLA-DQB1]) accounts for up to 40–50% of the familial clustering of type 1 diabetes.

HLA class II gene alleles are statistically the most strongly associated with type 1 diabetes, with good evidence that particular alleles of the HLA-DQA1, HLA-DQB1 (previously referred to as HLA-DR3/4) and HLA-DRB-1 loci are all primarily involved in the genetic predisposition to type 1 diabetes. Combinations of HLA-DQ genes, and particularly those present in HLA-DQ2/DQ8 heterozygotes, are linked with disease susceptibility. Indeed, approximately 30% of people with type 1 diabetes are HLA-DQ2/DQ8 heterozygotes. Conversely, other HLA-DQ alleles confer disease protection.

The insulin gene region (INS), which maps to chromosome 11p15.5 and is now designated IDDM2, is the only non-HLA gene to have been generally accepted as a genetic contributor to type 1 diabetes risk. It is a plausible candidate susceptibility locus because insulin may act as an autoantigen in the immune-mediated process leading to type 1 diabetes.

Environmental factors

The notion of implicating environmental factors in the pathogenesis of type 1 diabetes stems from rising global incidence, discordance rates in twins, geographic variability in incidence and rapid assimilation of incidence when individuals migrate from low- to high-incidence areas. It has been suggested that environmental factors could modify gene expression through epigenetic mechanisms, thus inducing an aberrant immune response and islet autoimmunity.

Identifying causative factors forms the basis of research into effective measures to prevent type 1 diabetes. Experimental and epidemiological studies have identified a number of potential factors that could be associated; however, linking causation to type 1 diabetes remains a challenge.

Viral infections are the most noted environmental factor in epidemiological studies. The rise in the global incidence of type 1 diabetes in colder months, when these viruses are more prevalent, as opposed to warmer ones, along with the discovery of enteroviral antibodies and increased levels of viral RNA in the pancreas and peripheral blood samples of individuals with type 1 diabetes, have formed the basis of this link. The strongest relationships are with Coxsackieviruses and mumps and rubella viruses. The precise role of these viruses in initiating autoimmunity or directly attacking β cells remains unclear.

Diet. Investigation of the relationship between gluten-triggered autoimmune damage of β cells and type 1 diabetes has shown encouraging results in animal models. However, human studies, including The Environmental Detriments of Diabetes in the Young³ study and Diabetes Autoimmunity Study in the Young,⁴ have not demonstrated risk conclusively and, if there is any association, it is in the first 4 months of