important in blastocyst development.
GLUT‐9 and 10: unclear functional significance.
Figure 5.17 (a) The structure of a typical glucose transporter (GLUT). (b) The intramembrane domains pack together to form a central hydrophilic channel through which glucose passes.
Most of the other GLUTs are present at the cell surface, but in the basal state GLUT‐4 is sequestered within vesicles in the cytoplasm. Insulin causes these vesicles to be translocated to the cell surface, where they fuse with the plasma membrane. The inserted GLUT‐4 unit then functions as a membrane pore that allows glucose entry into the cell. The process is reversible: when insulin levels fall, the plasma membrane GLUT‐4 is removed by endocytosis and recycled back into intracellular vesicles for storage (Figure 5.18).
In normal subjects, blood glucose concentrations are maintained within relatively narrow limits at around 5 mmol/L (90 mg/dL) (Figure 5.19). This is achieved by a balance between glucose entry into the circulation from the liver and from intestinal absorption, and glucose uptake into the peripheral tissues such as muscle and adipose tissue. Insulin is secreted at a low, basal level in the non‐fed state, with increased, stimulated levels at mealtimes (Figure 5.20).
At rest in the fasting state, the brain consumes about 80% of the glucose utilised by the whole body, but brain glucose uptake is not regulated by insulin. Glucose is the main fuel for the brain, such that brain function critically depends on the maintenance of normal blood glucose levels.
Figure 5.18 Insulin regulation of glucose transport into cells.
Figure 5.19 Profiles of plasma glucose and insulin concentrations in individuals without diabetes.
Insulin lowers glucose levels partly by suppressing glucose output from the liver, both by inhibiting glycogen breakdown (glycogenolysis) and by inhibiting gluconeogenesis (i.e. the formation of ‘new’ glucose from sources such as glycerol, lactate and amino acids, like alanine). Relatively low concentrations of insulin are needed to suppress hepatic glucose output in this way, such as occur with basal insulin secretion between meals and at night. With much higher insulin levels after meals, GLUT‐4 mediated glucose uptake into the periphery is stimulated.
Figure 5.20 Overview of carbohydrate metabolism. cats, catecholamines; cort, cortisol; glcg, glucagon; ins, insulin; NIMGU, non‐insulin mediated glucose uptake.
FURTHER READING
1 Drucker DJ, Habener JF, Holst JJ. Discovery, characterization and clinical development of the glucagon‐like peptides. J Clin Invest 2017; 127:4217–4227.
2 Fu Z, Gilbert ER, Liu D. Regulation of insulin synthesis and secretion and pancreatic Beta‐cell dysfunction in diabetes. Curr. Diabetes Rev. 2013; 9:25–53.
3 Henquin JC. Regulation of Insulin Secretion: A matter of phase control and amplitude modulation. Diabetologia 2009; 52:739–751.
4 Henquin JC, Dufrane D, Gmyr V, et al. Pharmacological approach to understanding the control of insulin secretion in human islets. Diab. Obes. Metab. 2017; 19:1061–1070.
5 Kojima I, Medina J, Nakagawa Y. Role of the glucose‐sensing receptor in insulin secretion. Diab. Obes. Metab. 2017; 19(Suppl. 1):54–62.
6 Rorsman P, Braun M. Regulation of insulin secretion in human pancreatic islets. Annu. Rev. Physiol. 2013; 75:155–179.
7 Tengholm A, Gylfe E. cAMP signalling in insulin and glucagon secretion. Diab. Obes. Metab. 2017; 19(Suppl. 1):42–53.
Chapter 6 Epidemiology and aetiology of type 1 diabetes
KEY POINTS
Type 1 diabetes is one of a number of autoimmune endocrine diseases with a genetic and familial basis, although the majority of cases occur sporadically.
Incidence rates vary from <5 to >60 per 100,000, generally being highest in northern latitudes.
These rates are increasing more rapidly than can be explained by genetic factors alone.
The autoimmune and genetic processes underpinning the disease are being unravelled.
Environmental factors such as viruses and diet are responsible for some of the increase.
Preventative trials have been disappointing but more targeted approaches are ongoing.
Introduction
The most common cause of type 1 diabetes (over 90% of cases) is T cell‐mediated autoimmune destruction of the islet β cells leading to a failure of insulin production. The exact aetiology is complex and still imperfectly understood. However, it is probable that environmental factors trigger the onset of diabetes in individuals with an inherited predisposition. Unless insulin replacement is given, absolute insulin deficiency will result in hyperglycaemia and ketoacidosis, which is the biochemical hallmark of type 1 diabetes. This is now sometimes termed type 1A. Type 1B or non‐autoimmune diabetes is also the result of an absolute insulin deficiency but from a range of possible causes such as monogenic diabetes (see Chapter 8) or pancreatic disease.
Epidemiology
There is a striking variation in the incidence of type 1 diabetes between and within populations. Part of the problem has been the lack of full case ascertainment in carefully defined populations. Historically, the highest incidence rates have been in Northern Europe, but rates are rapidly increasing in other regions such as the Middle East (Figure 6.1 and Table 6.1). The variation in incidence by geographical position in Europe is striking (Figure 6.2) and might reflect the impact of environmental factors. Incidence rates themselves have been increasing over the past three decades. In Europe the average rate of increase from 1989–2013 was 3.4% per annum reflecting a doubling in 20 years. However, the average hides considerable variation with rates of increase slowing in Scandinavia, Ireland, Italy, and Spain and some UK centres, and increasing in others (Poland, Romania, Lithuania, and Macedonia). Lower rates of increase in the decade 2002–2012 have been reported in in the USA (1.8% pa), Canada (1.3% pa)