What is the cause of the impaired secretory ability of the pcell in Type DM

The exact aetiology of impaired b-cell secretory ability is not completely elucidated, despite the large number of studies in animals and humans. Specific causes of impaired function can be a decrease in b-cell mass, an increased apoptosis/decreased regeneration of the b-cells, exhaustion of the b-cells secondary to compensatory hyperinsulinaemia (a consequence of long-term peripheral insulin resistance), glucotoxicity and/or lipotoxicity in the pancreas and amyloid deposition in large quantities inside the pancreatic cell. According to findings from the UKPDS (United Kingdom Prospective Diabetes Study), b-cell function was already decreased by 50 percent at the time of diagnosis of Type 2 DM and continued to deteriorate during the following years. Usual defects involve a decrease or absence of the first phase of insulin secretion in response to an intravenous glucose challenge, a decreased response to eating mixed meals, alterations in the pulsatile basal insulin secretion, a decrease in the second phase of insulin secretion, defective responsiveness of the b-cell to insulin-secretory stimuli other than glucose and an increase in the proportion of pro-insulin secretion. Recent studies have proven that b-cell mass is actually decreased in Type 2 DM and this is due to an increase in apoptosis (death) of the b-cells and not to decreased regeneration of the cells. The fact, however, that b-cell mass is decreased by only 20-30 percent in overt DM cannot explain the approximate 80 percent reduction in the functional capacity of the b-cell. This indicates the significance of functional disturbances in the secretory capacity of the b-cell and not simply a decrease in the number of the cells. This decreased mass and functionality of the b-cells precedes the clinical manifestation of DM and is evident even at the stage of pre-diabetes (impaired fasting glucose [IFG] and/or impaired glucose tolerance [IGT]). When b-cell mass decreases below a certain critical level and insulin production cannot compensate for the peripheral needs, hyperglycaemia ensues. A decrease in b-cell function by about 60 percent, in combination with existence of peripheral insulin resistance, is sufficient to cause hyperglycaemia.

This reduced functionality (qualitative and quantitative) of the b-cell is considered to be (as mentioned already) genetically predetermined, although the responsible genes have not yet been determined. Recent studies show that the increased apoptosis of the b-cells at the stage of overt DM is due to amyloid deposition inside the cells and to the effect of environmental factors (hyperglycaemia [glucotoxicity] and dyslipidaemia [lipotoxicity]) on b-cell function. In fact, a series of studies show that prolonged exposure of cultured human islets to high glucose levels and to saturated fatty acids increase b-cell apoptosis in a dose-dependent manner. However, monounsaturated fatty acids seem not to affect adversely islet function and their presence blunts the harmful effects of saturated fatty acids on the b-cell. Nevertheless, although increased apoptotic activity of the b-cells at the stage of overt DM can be explained (by gluco- and lipo-toxicity), it remains unclear what underlies the apoptotic loss of b-cells at the stage of pre-diabetes, before hyperglycaemia and dyslipidaemia ensues. The occurrence of apoptosis in patients with IFG suggests an inherent defect of the b-cell function, presumably of hereditary aetiology, in those people who are predisposed to later develop DM.

Delayed growth during endometrial or first infantile period has also been associated with increased chance of Type 2 DM development later in life, especially in those people who will become obese in their adulthood. It is thought that poor nutrition during endometrial life 'programmes' the b-cell to have reduced responsiveness on extracellular glucose concentrations and leads later to increased apoptosis, especially if insulin resistance develops, as is the case with obesity. However, the fact that DM does not develop in all persons with delayed endometrial growth implies that this element is only one of the events that ultimately lead to disease occurrence.

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