β-Cell Failure or β-Cell Abuse?

Abstract

This review is motivated by the need to question dogma that has not yielded significant improvements in outcomes of Type 2 Diabetes treatment: that insulin resistance is the driver of ß-Cell failure and resulting hyperglycemia. We highlight the fact that hyperlipidemia, insulin resistance, and hyperinsulinemia all precede overt diabetes diagnosis and can each induce the other when tested experimentally. New research highlights the importance of high levels of circulating insulin as both a driver of weight gain and insulin resistance. Data from our lab and others document that several nutrients and environmental toxins can stimulate insulin secretion at non-stimulatory glucose in the absence of insulin resistance. This occurs either by direct action on the ß-Cell or by shifting its sensitivity to known secretagogues. We raise the next logical question of whether ß-Cell dysfunction in Type 2 Diabetes is due to impaired function, defined as failure, or if chronic overstimulation of the ß-Cell that exceeds its capacity to synthesize and secrete insulin, defined as abuse, is the main abnormality in Type 2 Diabetes. These questions are important as they have direct implications for how to best prevent and treat Type 2 Diabetes.

Keywords: beta-cell; hyperinsuilnemia; insulin resistance; obesity; type 2 diabetes.

Figure 1

Basal (fasting) and glucose-stimulated insulin secretion (GSIS) rates in lean, obese, patients with impaired glucose tolerance (IGT) and diabetics (T2D). Data redrawn from Ferrannini et al. (17), showing increasing percentage of basal insulin secretion rate relative to total insulin secretion rate and diminishing GSIS in IGT and T2D. Number above each bar represents the ratio of GSIS to basal insulin secretion rate.

Figure 2

Relationship between lipid stores, insulin secretion, and insulin content in INS1 (832/13) cells cultured in the presence of different nutrients: 1, 4 mM glucose for more than 2 weeks (chronic) (n = 12); 2, 4 mM glucose for 48 h (n = 8); 3, 4 mM glucose chronic + 0.15 mM oleate for 24 h (n = 6); 4, 11 mM glucose (n = 13); 5, 11 mM glucose + 0.15 mM oleate for 48 h (n = 4). As standard culture media glucose concentration for INS1 cells is 11 mM, cells identified as being cultured in 4 mM glucose were switched from 11 to 4 for the stated period of time. Lipid content was measured using Nile Red. (A) Relationship between Insulin secretion at 4 mM glucose following washout of growth media and lipid stores. (B) Correlation of intracellular lipid stores and insulin secretion at 12 mM glucose. (C) Relationship between lipid stores and total insulin content. Data in this figure were recalculated from previously published results (7).