Loss of first- phase insulin secretion is an early feature of β- cell dysfunction. Individuals with isolated impaired fasting glucose show a decrease in first- phase insulin- secretory response to intravenous glucose and early- phase insulin response to oral glucose. The late- phase insulin response after an oral glucose tolerance test is less severely impaired than in people with impaired glucose tolerance who have severe defects in both early- and late- phase insulin responses. First- phase insulin secretion plays an important role in priming the liver to inhibit endogenous glucose production in response to glucose or nutrient ingestion. Therefore, the defect in early- phase insulin secretion in impaired fasting glucose and impaired glucose tolerance results in inadequate suppression of hepatic glucose production and contributes to an excessive early rise in plasma glucose in response to an oral glucose load. In people with impaired glucose tolerance, the combination of deficient second- phase (late- phase during oral glucose tolerance test) insulin secretion and peripheral insulin resistance translates into less efficient glucose disposal. As a result, after the ingestion of a glucose load, plasma glucose concentration will continue to increase after the initial 60 minutes to remain elevated after 120 minutes. The loss of first- phase insulin not only contributes to impaired hepatic glucose metabolism, but also is an independent predictor of the development of type 2 diabetes.

In summary, the natural course of β- cell function suggests that the acute insulin response and glucose sensitivity play a major role in determining glucose tolerance. Longitudinal studies of the Pima relating changes in insulin sensitivity and acute insulin response have clearly demonstrated that it is the worsening of the latter rather than the development of insulin resistance that marks the progression from normal glucose tolerance to impaired glucose tolerance and, eventually, type 2 diabetes.

The extent to which these functional abnormalities are also linked to loss of β- cell mass is still a matter of discussion, but β cells can undergo various changes, a phenomenon known as β- cell plasticity. Recent evidence has shown how in people with pre- diabetes, under the increased demand imposed by insulin resistance, islets and exocrine cells become extraordinarily plastic. Although an increased β- cell workload is a risk factor for hyperglycaemia, in most individuals there is an adaptive increase in insulin and proinsulin secretion with no apparent β- cell failure. Rather, insulin resistance in these individuals induces an increase in the β- cell area, as observed in pancreas samples obtained from people without diabetes. Neogenesis from duct cells and/or trans- differentiation from α cells are likely explanations for the changes in β- cell mass observed in people with insulin resistance.

Assessment of β- cell mass is largely dependent on methodological approaches, but several reports claim that an apparent reduction in β- cell volume of up to 60% is present in individuals with pre- diabetes. The decrease in β- cell mass has been traditionally attributed to an increased rate of apoptosis and, to a lesser extent, autophagy. An increase in β- cell death occurs without a compensatory increase in β- cell replication owing, at least in part, to the limited regenerative capacity of adult human β cells. Along with these mechanisms, β- cell dedifferentiation, rather than cell death, accounts for the loss of β cells in the pancreatic islet of individuals with diabetes. Figure 1 summarizes the mechanisms involved in β- cell plasticity.

Fig1. Schematic representation of the hypothetical scenario of islet plasticity. Islet plasticity is the capacity of the islet to modify its morphology and function according to different metabolic conditions. A potential explanation of the present scenario is as follows: when insulin resistance increases insulin demand, islet plasticity guarantees a twofold increase in β cells, whose origins are still debated, but some hypotheses are trans- differentiation from centroacinar and duct cells (duct red cells and centroacinar violet cells), replication (red cell Ki67+), and neogenesis from an unknown source (white to red cell); a twofold increase in the α cells trans- differentiated into insulin- producing cells (yellow double- positive cells); and a fivefold increase in the α cells via neogenesis, with a consequent increase of a potential glucagon- like peptide 1 (GLP- 1) source (white to green cell). As with any compensatory mechanism, in a chronic condition it is bound to fail. The exhausted β cells undergo dedifferentiation (Dedif; a resting state, red to grey cells), the double- positive cell switches back into the original α cell (yellow cells to green cells), and the overstressed β cells trans- differentiate into α cells (red cell to green cell). Gcg, glucagon; Ins, insulin. Source: Mezza et al..

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مواضيع ذات صلة

Physiological insulin secretion

Hypoglycemia in Diabetes

Mouse genetics reveal tissue- integrated insulin signalling

Heterologous regulation and insulin resistance

Abnormalities of glucagon secretion and action in diabetes

Glucagon intra- islet communication and insulin secretion

Glucagon actions in the liver: amino acid metabolism and the hepatic–α- cell axis

Glucagon actions in the liver: glucose and lipid metabolism

Regulation of α- cell secretion

Regulation of insulin secretion by non- nutrients

Regulation of insulin secretion

Islet structure and function