Impaired β-Cell Function, Incretin Effect, and Glucagon Suppression in Patients With Type 1 Diabetes Who Have Normal Fasting Glucose

Abstract

We have recently described a novel phenotype in a group of subjects with type 1 diabetes that is manifested by glucose >11.1 mmol/l 120 min after an oral glucose load, but with normal fasting glucose levels. We now describe the metabolic characteristics of these subjects by comparing parameters of islet hormone secretion and glucose disposal in these subjects to age-matched nondiabetic control subjects. The patients with type 1 diabetes had fasting glucose, insulin, and glucagon values similar to those of control subjects. Additionally, the insulin secretory response to intravenous arginine at euglycemia was similar in the control and diabetic groups (264 ؎ 33.5 and 193 ؎ 61.3 pmol/l; P ‫؍‬ 0.3). However, marked differences in ␤-cell function were found in response to hyperglycemia. Specifically, the first-phase insulin response was lower in diabetic subjects (329.1 ؎ 39.6 vs. 91.3 ؎ 34.1 pmol/l; P < 0.001), as was the slope of glucose potentiation of the insulin response to arginine (102 ؎ 18.7 vs. 30.2 ؎ 6.1 pmol/l per mmol/l; P ‫؍‬ 0.005) and the maximum insulin response to arginine (2,524 ؎ 413 vs. 629 ؎ 159 pmol/l; P ‫؍‬ 0.001). Although plasma levels of glucagon-like peptide (GLP)-1 and gastric inhibitory peptide (GIP) did not differ between control and diabetic subjects, the incretin effect was lower in the diabetic patients (70.3 ؎ 5.4 vs. 52.1 ؎ 5.9%; P ‫؍‬ 0.03). Finally, there was a lack of suppression of glucagon in the patients after both oral and intravenous glucose administration, which may have contributed to their postprandial hyperglycemia. Glucose effectiveness did not differ between patients and control subjects, nor did insulin sensitivity, although there was a tendency for the patients to be insulin resistant (9.18 ؎ 1.59 vs. 5.22 ؎ 1.17 pmol ⅐ l -1 ⅐ min -1 ; P ‫؍‬ 0.08). These data characterize a novel group of subjects with type 1 diabetes manifested solely by hyperglycemia following an oral glucose load in whom islet function is normal at euglycemia, but who have marked defects in both ␣-and ␤-cell secretion at hyperglycemia. This pattern of abnormalities may be characteristic of islet dysfunction early in the development of type 1 diabetes. Diabetes 51:951-957, 2002

Glucagon Response to Oral Glucose Challenge in Type 1 Diabetes: Lack of Impact of Euglycemia

“…Previous studies have demonstrated that, in patients with T1D, a paradoxical increase in glucagon occurs in response to an oral glucose challenge (2,8,11). However, these reports have not accounted for the potential effect of prechallenge ambient glycemia and appropriate insulinemia, which could result in differential glucagon responses.…”

“…Indeed, impaired suppression of glucagon after oral ingestion of glucose has been demonstrated in both type 1 diabetes (T1D) and type 2 diabetes (T2D) (2)(3)(4), suggesting that hyperglucagonemia develops in parallel with hypoinsulinemia. Thus, in addition to insulin deficiency, defects in glucagon physiology may be involved in potentiating fasting and postprandial hyperglycemia in diabetes (5).…”

Glucagon-like peptide 1 (1–37) converts intestinal epithelial cells into insulin-producing cells

“…Tissue-specific processing leads to the formation of several similar analogs. GLP-1-(7-36) and GLP-1-(7-37), secreted from enteroglucagon-producing cells (L cells) in the intestinal mucosa during hyperglycemia (15)(16)(17), are potent intestinal insulinotropic hormones that augment insulin secretion (18) and acutely lower glucose levels in rodents and in both type 1 and 2 human diabetic subjects (19)(20)(21)(22). In contrast to these well characterized molecules, GLP-1-(1-37), formed in very small amounts by pancreatic glucagon-producing ␣ cells, has little effect on insulin release (23).…”

The Gly972→Arg IRS-1 Variant Is Associated With Type 1 Diabetes in Continental Italy

“…Whereas type 2 diabetes is clearly characterized by gradual loss of insulin secretion, the insulin deficit in type 1 diabetes is the result of more or less massive and rapid autoimmune destruction of the ␤-cell mass (1,13). However, a recent report indicates that in the early stages of the disease, certain type 1 diabetic patients show some degree of ␤-cell dysfunction, manifested primarily by hyperglycemia after glucose loading due to a defective insulin secretion (17). Interestingly, a similar impairment in insulin secretion has also been observed in the IRS-1 null mice, both in vivo and in vitro (18).…”