[ Diabetes Solutions ]

Insulin Resistance Compensation: Not Just a Matter of β-Cells?

One of the distinguishing features of vertebrate development is its highly regulative nature. In this study, we sought to determine the factors associated with exaggerated glucagon secretion in response to an arginine challenge in patients with type 1 and type 2 diabetes. In the isolated perfused pancreas of normal rats, isoprenaline (0.01 microM) or forskolin (1 microM) induced a +200 to +300% increase of glucagon secretion and a 20 to 30% increase of pancreatic vascular flow rate. In type 2 diabetes mellitus (T2DM), beta-cell insulin response to glucose is blunted, including absence of early acute response, and alpha-cell response to glucose is impaired, resulting in absolute or relative hyperglucagonaemia and inappropriate hepatic glucose output that contributes to fasting hyperglycaemia. Herrera, demonstrated that beta cells will spontaneously regenerate after near-total beta cell destruction in mice and the majority of the regenerated beta cells are derived from alpha cells that had been reprogrammed, or converted, into beta cells. In this article, we describe the effects of tolbutamide and diazoxide on [Ca2+]i in alpha-, beta-, and delta-cells within intact islets of Langerhans. With the advent of islet transplantation protocols, scientists are on the cusp of freeing patients from insulin injections and/or pharmacological intervention.

This mechanism of action is unique in that no other approved antidiabetic drugs act via this mechanism, and raises the prospect that selective Nav1.3 blockers may constitute a novel approach for the treatment of diabetes. In conclusion, in the development of early to late diabetes, there is a down-regulation of P2X7 receptors on islet cells and a loss of alpha- and beta-cell populations. The cross-sectional nature of the studies, the potential interference of pre- and postmortem processes, and the absence of concomitant or even previous assessment of insulin resistance and insulin secretion are significant limitations of the available morphological studies. Produced by the alpha cells in the pancreas, glucagon acts on the liver to help raise blood glucose when it becomes low. (13) present a detailed analysis of islet function, insulin resistance, and islet morphology in 18 nondiabetic patients requiring a pancreatoduodenectomy (∼50% pancreatectomy) to treat a tumor of the ampulla of Vater. One week before surgery a hyperinsulinemic-euglycemic clamp, a hyperglycemic clamp followed by acute stimulation with L-arginine, and a mixed-meal test were performed. Based on the hyperinsulinemic-euglycemic clamp, patients were divided into more insulin-sensitive and more insulin-resistant.

“As well as new approaches to research against cancer, the investigation of mechanisms responsible for transdifferentiation revealed in this article, will allow a better understanding of the biology of pancreatic endocrine cells and the design of new strategies for regeneration of pancreatic beta cells, a major challenge in the treatment of diabetes” concludes Chang Xian Zhang. Mean islet size and fractional insulin, glucagon, and somatostatin areas were higher in insulin-resistant subjects. β-Cell replication, apoptosis, and individual β-cell size were similar in insulin-resistant and insulin-sensitive subjects, suggesting that these factors did not contribute to increase β-cell mass. In contrast, increased islet neogenesis was suggested in insulin-resistant subjects based on higher β-cell and islet densities and on indirect markers of neogenesis that are compatible with a ductal origin of new β-cells. Insulin-resistant subjects showed a dramatic increment of fractional α-cell area that correlated inversely with insulin sensitivity, a reduced β-/α-cell ratio, and an increased percentage of cells double-positive for insulin and glucagon. As shown in the table below, standardised clamp procedures might be helpful to evaluate insulin resistance, alpha and beta cell function in patients with T2DM. The simultaneous and comprehensive functional study and morphological analysis of islets in pancreas from living subjects is a major strength of the study.

The increased β-cell mass in insulin-resistant subjects is in line with current concepts about β-cell plasticity and compensation for insulin resistance. Among the several possible origins of the increased β-cell mass (Fig. 1), Mezza et al. support a role for islet neogenesis that some previous studies have also suggested (14). The increased percentage of cells double-positive for the duct marker CK19 and insulin indicates that neogenetic β-cells could be of ductal origin. Nevertheless, in the absence of direct markers, islet cell neogenesis cannot be confirmed (14). The identity of the circulating signals that drive the compensatory β-cell response to insulin resistance is of fundamental interest.

A dominant role has been proposed for glucose (15), but other factors have been identified in rodents (16). This question was not addressed in the current study. Adult β-cell mass expansion in response to increased insulin demand, such as that generated by insulin resistance, may take place based on preexisting β-cells—by enhanced β-cell replication and/or increased individual β-cell size—or new β-cells could be generated from other cell sources, such as neogenesis from ductal cells or transdifferentiation from acinar cells or α-cells. In diabetic patients, β-cell mass reduction can result from increased apoptotic cell death, and recently β-cell dedifferentiation and conversion into other endocrine non–β-cells of the islets has been described in diabetic mice. The sixfold increment in α-cell area in insulin-resistant subjects of a higher magnitude than that of β-cells and the proposed role of pancreatic α-cells in GLP-1 secretion and in β-cell mass compensation generate new questions about α-cell involvement in insulin resistance and in the evolution toward type 2 diabetes. Could the increased α-cell area be part of the compensatory response to insulin resistance? There is research that shows the cells that line the ducts of the pancreas can convert to beta cells.

On the other hand, β-cell dedifferentiation and conversion into other islet endocrine cell types was recently described in diabetic mice (19). It is intriguing to consider whether β-cell dedifferentiation and conversion into α-cells could occur in insulin-resistant subjects and play a role in the progressive loss of β-cell function and mass that leads to the development of diabetes. However, at this time, caution should be used when interpreting the α-cell results: α-cell area was unusually low in the insulin-sensitive group (less than 7% of the β-cell area); glucagon secretion was not increased in the insulin-resistant group, despite the higher α-cell area; and in other studies, increased α-cell mass has not been identified in obese subjects (12,20). The cross-sectional nature of the morphological study, the small number of patients in each group, and the assessment of cell mass as fractional area instead of absolute cell mass are additional limitations of the study. In summary, the results of Mezza et al. (13) strongly support the capacity of human β-cells to respond to the increased demands imposed by insulin resistance, and they provide indirect evidence suggesting that neogenesis from duct cells contributed to increased β-cell mass. The increased α-cell area identified in the normoglycemic insulin-resistant subjects, as well as the involvement of GLP-1, if confirmed, could open new possibilities to prevent the evolution to type 2 diabetes.

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