Hyper- and hypoinsulinemia in type-2 diabetes: What may be wrong in the secretory mechanism of the B-cell

Abstract

Type-2 diabetes frequently is the consequence of overnutrition causing overweight, which then produces insulin resistance. The following hyperglycemia induces permanent overstimulation of the insulin secretory machinery of the B-cell, which results in hyperinsulinemia and/or hypoinsulinemia. The mechanisms, however, of these disturbances are not understood so far. Animal models, which can be used to solve these questions, are, among others, long-term incubation of pancreatic islets in culture in the presence of high glucose and/or long-term infusion of rats with glucose. Using these models sensitization [Bedoya and Jeanrenaud, 1991; Leahy et al., 1987; Purrello et al., 1992; Thams, 1991; Thibault et al., 1993; Timmers et al., 1990] and/or desensitization of insulin release [Bedoya and Jeanrenaud, 1991; Leahy et al., 1987; Davalli et al., 1992; Eizirik et al., 1992; Bolaffi et al., 1988; Timmers et al., 1990] have been reported. Whether or not there is sensitization or desensitization depends on the glucose concentration [Eizirik et al., 1992; Leahy et al., 1986; Sako and Grill, 1990] and the duration of glucose action [Bedoya and Jeanrenaud, 1991; Bolaffi et al., 1988]. Both, sensitization and desensitization, appear to be reversible on return to normal glucose or mild hypoglycemia [Leahy and Weir, 1991; Svenson and Hellerström, 1991]. It seems, however, that there is a fluent change from the first occurring hyperinsulinemia to hypoinsulinemia. In this lecture I first want to talk about the possible mechanism of sensitization of insulin secretion discussing previous results we have obtained from rat islets isolated after a 48 hours period of i.v. infusion with 50% glucose. In the second part I will discuss some of the findings coming from the respective literature concerning desensitization of insulin secretion.

The Role of Obesity, Type 2 Diabetes, and Metabolic Factors in Pancreatic Cancer: A Mendelian Randomization Study

“…The latter observation would be in line with some studies suggesting that the observational association between type 2 diabetes risk may be due to reverse causation, that is, type 2 diabetes reflecting an early manifestation of pancreatic cancer, rather than being a causal factor ( 14 , 15 ). As our results suggest a potential important causal role of fasting insulin, the occurrence of hyperinsulinemia in early type 2 diabetes ( 46 ) would also be in line with insulin acting as a confounder for any observed association between type 2 diabetes and pancreatic cancer risk.…”

Diabetes and risk of pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium

“…One might expect a longer exposure to diabetes to be associated with higher cancer risk; however, type 2 diabetes begins with insulin resistance and relative hyperinsulinemia. Later in the natural history, there is further loss of the islet β-cells, resulting in hypoinsulinemia [34]. If insulin levels contribute to diabetes and act as an independent risk factor for pancreatic cancer, then it follows that patients with a longer duration of diabetes, who are more likely to be hypoinsulinemic, would be at lower risk compared to those who are earlier in their diabetes natural history and have higher serum insulin levels.…”

“…The relationship between diabetes and pancreatic cancer risk is further complicated by the potential for pancreatic cancer to cause diabetes [34]. Thus, it is vital in studies of risk to exclude any patient in whom diabetes has been caused by pancreatic cancer.…”