Diabetes

a metabolic disorder in which there is persistent hyperglycaemia in the body

beta cell dysfunction due to decreased insulin secretion

• increased thirst (polydipsia) • increased fatigue • increased urination (polyuria) • blurred vision

• monogenic • type 1 • type 2

• MODY • neonatal • mitochondrial • syndromes of insulin resistance

an autosomal dominant disorder that usually occurs before the age of 25

affect the pancreatic β cell

• MODY1 – early pancreatic development and insulin secretion defects • MODY2 – mild • MODY3 – insulin secretion defects; complications occur • MODY5 – pancreatic hypoplasia; renal dysfunction

a maternally inherited disorder caused by a rare genetic defect in the mitochondria that impairs insulin production

mutations in the insulin receptor

• type A insulin resistance e.g. Donohue syndrome, Leprechaunism, Rabson-Mendenhall syndrome • decreased number of insulin receptors • impaired insulin binding • impaired tyrosine kinase activity

an autoimmune-mediated destruction of pancreatic beta cells

autoantibodies that attack the pancreatic beta cells

• islet cell antibodies (ICA) • glutamic acid decarboxylase (GAD65) • insulin autoantibodies (IAA) • protein tyrosine phosphatase IA-2 • zinc transporter 8 (ZnT8)

• genetic susceptibility and environmental factors (viruses, bacteria, chemicals) initiate the process • immune activation – CD8 T-cells kill β-cells, and inflammation reduces regulatory T-cell function • autoantibody production – B cells produce autoantibodies, with CD4 T-cell help • epitope spreading – new β-cell antigens are released, amplifying the immune attack • clinical diabetes – loss of β-cell mass causes hyperglycaemia, with a temporary “honeymoon phase” of partial β-cell function recovery

diabetes during pregnancy when the body cannot produce enough insulin to meet the increased demands

asymptomatic and resolved after pregnancy

• genetic factors e.g. TCF7L2, HHEX, CDKN2A • modifiable factors e.g. obesity, weight gain, smoking and diet • reproductive and medical history • foetal factors

developing type 2 diabetes and related vascular disorders or other comorbidities in later life

a chronic condition that occurs when the body doesn’t produce enough insulin or doesn’t use insulin properly; often coincides with early development of peripheral insulin resistance

if pancreatic beta cells fail to compensate for insulin resistance

impaired insulin secretion and subsequent hepatic glucose production

• fuel storage and inhibition of breakdown of stored fuel in skeletal muscle, liver and adipose tissue • recruitment of glucose transporters to the plasma membrane for glucose transport into skeletal muscle and adipose tissue

• metabolic enzymes • intracellular metabolites • gene expression