01 September 2018
There are four main cell types of the endocrine pancreas: α, β, δ, and pancreatic peptide (PP) cells, which secrete glucagon, insulin, somatostatin, and pancreatic peptide, respectively.
D1 cells and enterochromaffine cells make up a much smaller portion of the endocrine pancreas but play a role in elaboration of vasoactive intestinal polypeptide (VIP) (inducing glycogenolysis and gastrointestinal fluid secretion) and serotonin. Enterochromaffin cells are the source of pancreatic tumors that cause carcinoid syndrome.
Diabetes mellitus defines a group of disorder that all share hyperglycemia as a consequence and can continue to cause multi-organ system end organ failure:
Normal blood is within the set [70, 120] mg/dL. Diabetes is defined by the ADA and WHO repeated test showing that meet one of the following criteria:
Most cases fall into one of the two following classes:
During fasting states, blood glucose levels are maintained primarily by hepatic glucose output. Low insulin and high glucagon has the effect of stimulating hepatic gluconeogenesis, gycogenolysis, and inhibition of glycogen synthesis all of which prevents hypoglycemia.
After eating a meal, high insulin and low glucagon in response to higher levels of circulating glucose. The effect if increase up take of glucose by skeletal muscle,
Preproinsulin is synthesized and transported to the golgi complex where it is cleaved into proinsulin. Proinsulin is cleaved into insulin and C-peptide and stored in secretory vesicles. Because the are secreted in equimolar quantities, C-peptide is used a measure of β cell mass in type 1 diabetes and increasing resistance-associated hyperinsulinemia.
GLUT-2 transporters in β cells uptake independent of insulin concentration. Mitochondrial metabolism of glucose produces ATP, which inhibits efflux of K+ via a ATP-sensitive K+ channel. This channel also a sulfonylurea receptor subunit, which is the target of <++> used for treatment.
Increasing concentrations of K+ causing membrane depolarization and influx of Ca2+ via voltage-gated calcium channels. Increasing intracellular Ca2+ levels causes immediate exocytosis of insulin vesicles. Sustained signaling of the secretory response eventually triggers active synthesis of insulin.
A second class of hormones incretins also play important roles in regulation in the response to a meal: Glucose-dependent insulinotropic polypeptide (GIP) is secreted to K cells in the proximal duodenum and glycagon-like peptide-1 (GLP-1) is secreted by L cells in the distal ileum and colon. Together, they:
GIP and GLP-1 are degraded by dipeptidyl peptidases (DPP) namely DPP-4. GLP-1 receptor agonists and DPP-4 inhibitors are a major target of new treatment development.
The main action of insulin is to promote glucose uptake in striated muscle where it is oxidised into important metabolic intermediates, used to make ATP, and promotes protein anabolism (and inhibits catabolism). In adipocytes, it promotes glucose uptake, its storage as fat, and inhibit fat catabolism. It also has mitogenic functions promoting cell growth and differentiation. One tissue, the brain, is notably insulin independent.
Insulin allows for dimerization of α and β subunits of the insulin receptor. The α subunit activates the tyrosine kinase activity of the β subunit’s cytosolic domain causing autophosphorylation and subsequent phosphorylation cascade of insulin receptor substrates IRS1-IRS4 and GAB-1, which result in activation of signaling cascades, including MAP kinase and PI3K. The latter pathway is responsible for activation of AKT (and CBL), which promote trafficking and docking of vesicles containing GLUT-4 transporters with the plasma membrane
Genetic susceptibility. There are more that 30 variant loci that are associate with type 1 diabetes mellitus but over 50% of the genetic susceptibility is associated to an HLA cluster on chromosome 6p21. Various combinations of HLA-DR3, DR4, or DQ8 confer increased risk. Polymorphisms in variable number of tandem repeats (VNTRs) region in the gene coding for insulin is also associated with increased risk.
Enviornmental factors. Molecular mimicry due to viral infections has also been proposed as a mechanism development of autoimmunity.
Mechanism of β cell distruction. The fundamental cause of development of autoimmunity is a failure of self-tolerance in T cells specific for islet antigens. The failure could be due to survival of auto-reactive T cells or defects in the function of regulatory T cell to suppress auto-reactive effector T cells. Sensitization to
is believed to occur in pancreatic lymph nodes. TH1 cells and C8+ cytotoxic T lymphocytes have be implicated in secreting IFN-γ and TNF that injure β cells are directly inducing apoptosis, respectively.
Genetic suseptability.