- inhibition of glycogenolysis via inhibition of glycogen phosphorylase and stimulation of glycogen synthase
- increased glucose uptake into adipocytes and skeletal muscle cells by activation of phosphoinositide 3 kinase and translocation of the glucose transporter GLUT4 from the cytoplasm to the cell membrane
- increased glycolysis (glucose breakdown) in adipocytes and skeletal muscle cells by increasing the activity of hexokinase and 6-phosphofructokinase.
Insulin also has paracrine effects on the neighbouring islet cells. Insulin reduces glucagon secretion by the alpha cells. This in turn increases the metabolic effects of insulin since glucagon normally stimulates glycogenolysis and gluconeogenesis by the liver and kidney.
Other actions of insulin
In addition to its metabolic effects, insulin can also affect steroidogenesis, vascular function, fibrinolysis, growth regulation and cancer (e.g. colorectal, ovarian and breast cancer). The latter effect may be mediated through both anabolic effects on protein and lipid metabolism, and interactions with other mediators of growth e.g. insulin-like growth factors 1 and 2 and their receptors. Insulin resistance and hyperinsulinaemia (e.g. in polycystic ovary syndrome) may stimulate ovarian androgen secretion by stimulating luteinizing hormone release or increasing ovarian luteinizing hormone receptors.
Diabetes mellitus
Diabetes mellitus comprises a group of common metabolic disorders that share the phenotype of hyperglycaemia (see ‘Diagnosis of diabetes mellitus’, below).
Presentation
Patients with diabetes may present with:
- fatigue
- polyuria, polydipsia and nocturia
- recent weight loss (less frequently in type 2 than in type 1 diabetes)
- diabetic ketoacidosis or hyperosmolar hyperglycaemic state (see Chapter 36)
- microvascular complications (retinopathy, nephropathy, neuropathy)
- macrovascular complications (ischaemic heart disease, stroke, peripheral vascular disease)
- recurrent infections.
Many patients with type 2 diabetes are asymptomatic at presentation and are identified by screening.
Classification and pathogenesis of diabetes mellitus
Type 1 diabetes
Type 1 diabetes mellitus is caused by destruction of the pancreatic insulin-producing beta cells, resulting in absolute insulin deficiency. The beta cell destruction is caused by an autoimmune process in 90% of patients with type 1 diabetes. This process progresses over a latent period (many months or years) during which the individual is asymptomatic and euglycaemic. This reflects the large number of functioning beta cells that must be lost before hyperglycaemia occurs.
A number of pancreatic beta cell autoantigens may play a role in the initiation or progression of autoimmune islet injury. These include glutamic acid decarboxylase (GAD), insulin and insulinoma-associated protein (IA-2). The cation efflux zinc transporter (ZnT8) has recently been recognized as another candidate type 1 diabetes autoantigen. However, it is not clear which of these autoantigens is involved in the initiation of the injury, and which is released only after the injury.
Type 1 diabetes is likely to occur in genetically susceptible subjects and is probably triggered by environmental agents.
Polymorphisms of a number of genes may influence the risk of type 1 diabetes. These include the gene encoding preproinsulin and a number of genes related to immune system function such as those for HLA-DQ alpha, HLA-DQ beta and HLA-DR (encoding class II major histocompatibility complex molecules, which present antigens to T lymphocytes), PTPN22 (lymphoid protein tyrosine phosphatase, a suppressor of T cell activation) and cytotoxic T lymphocyte antigen (CTLA-4).
Several environmental factors have been suggested to trigger the autoimmune process in type 1 diabetes. However, none has been conclusively linked to diabetes. Factors include pregnancy-related and perinatal influences, viruses (e.g. cox-sackie, rubella) and dietary factors (e.g. bovine milk proteins, cereals and omega-3 fatty acids).
Type 2 diabetes
Type 2 diabetes is characterized by increased peripheral resistance to insulin action, impaired insulin secretion and increased hepatic glucose output. Both genetic and environmental factors contribute to the development of insulin resistance and relative insulin deficiency in type 2 diabetes.
A genetic influence on the development of type 2 diabetes is supported by the following observations:
- Monozygotic twins have a 90% concordance rate.
- 40% of patients with type 2 diabetes have at least one parent with type 2 diabetes.
- The lifetime risk for a first-degree relative of a patient with type 2 diabetes is 5–10 times higher than for those without a family history of diabetes.
Monogenic causes of type 2 diabetes represent a very small fraction of cases (Box 34.1). It is likely that multiple genetic anomalies at different loci confer varying degrees of predisposition to type 2 diabetes. Several inherited polymorphisms have been identified which individually contribute only small degrees of risk for diabetes (see below).
The gene for the protease calpain 10 may confer major susceptibility to type 2 diabetes in Mexican-American individuals.
Peripheral insulin resistance
Obesity causes peripheral resistance to insulin-mediated glucose uptake and may also decrease the sensitivity of the beta cells to glucose. Upper body or male-type obesity has a much greater association with insulin resistance than lower body or female-type obesity. The mechanism by which obesity induces insulin resistance is poorly understood. The c-Jun amino-terminal kinase (JNK) pathway may be an important mediator of the relationship between obesity and insulin resistance as JNK activity is increased in obesity and can interfere with insulin action.
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