Clinical Gems

Transport of proinsulin from the ER to Golgi apparatus: After proinsulin is translocated into the lumen of the ER, it is then delivered in transport “COP-coated vesicles” to the cis-Golgi apparatus. Up until relatively recently, it was thought that newly synthesized proinsulin was passed from the cis-Golgi network “stack” via the medial- to the trans-stack of the Golgi apparatus stacks in “COP”-coated vesicles,

Insulin biosynthesis: the previous section outlines that insulin gene transcription is a highly controlled process. The product of this process, pre-proinsulin mRNA, is unusually stable in pancreatic beta cells and it is further stabilized as glucose concentrations increase. As such, there is normally an abundant source of preproinsulin mRNA in the beta-cell cytosol available for translation.

Dysregulation of the insulin gene: There is convincing evidence that abnormalities in insulin gene sequence or function play a role in pancreatic beta-cell dysfunction in type 2 diabetes. Abnormalities in the insulin gene structure consist of rare control region mutations, while insulin gene expression appears to be reduced by metabolic conditions associated with the diabetic state.

Glucose regulation of insulin gene transcription factors: Pdx-1 is mainly localized at the nuclear periphery at low glucose concentrations (1–2mM) in beta cells, and becomes phosphorylated and shuttles into the nucleus in response to concentrations stimulating insulin secretion.

The unique property of the pancreatic beta cell is its ability to secrete insulin to enable circulating glucose levels to be maintained within a narrow physiologic range, despite wide fluctuations in energy intake and expenditure.

Chronically elevated glucose and/or free fatty acids: type 2 diabetes is characterized by increased circulating nutrients including glucose and free fatty acids (FFA).The literature clearly shows that chronic exposure of beta cells to elevated glucose results in impaired beta-cell function, but the data regarding cellular toxicity in response to this nutrient are more mixed.

Disturbances in pancreas/islet morphology in diabetes: Type 1 diabetes (T1DM) is classically associated with autoimmune destruction of beta cells. However, the pancreas is more broadly affected, with overall pancreas size being decreased in individuals with this form of diabetes, and loss of exocrine tissue occurring close to areas of immune infiltration.

Islet vasculature: The islet is richly vascularized; while islets comprise only ∼2% of pancreas volume, they receive approximately 15% of the blood flow. Arterioles enter the islet and branch into tortuous capillaries, which have been suggested to contact almost every endocrine cell in the islet. These then converge on collecting venules outside the islet.

The pancreas is located in the upper abdominal cavity, in close proximity to both the duodenum and spleen. In humans, pancreatic weight ranges from 40–150 g. Embryonically, the pancreas develops from two separate buds of the primitive foregut, yielding duodenal (ventral) and splenic (dorsal) lobes.

For many years it was speculated that beta cells, much like neurons, were postmitotic and that their turnover in the mammal was minimal or zero. Over the last two decades, studies in mice have suggested a more dynamic picture, wherein beta-cell mass can change in response to physiologic states such as growth, pregnancy, and obesity.