Do sodium‐glucose transporter‐2 inhibitors increase plasma glucagon by direct actions on the alpha‐cell? – and does the increase matter for the associated increase in endogenous glucose production?

Mutations of HNF-1alpha lead to severe beta cell dysfunction, resulting in decreased glucose-induced insulin secretion. HNF-1alpha is also expressed in liver, kidney and pancreatic alpha cells, but the functional consequences of HNF-1alpha mutations in these organs remain unknown. We therefore assessed the counterregulatory responses to hypoglycemia in six patients with HNF-1alpha mutations (MODY3), five patients with non-insulin-dependent diabetes mellitus (NIDDM) and in nine healthy controls. Plasma glucagon concentrations and endogenous glucose production were measured every 15 min during a hyperinsulinemic clamp with progressive hypoglycemia. Plasma glucagon concentrations were similar at basal glycemia (73+/-6, 69+/-5 and 69+/-7 ng/l) and reached peak values of 88+/-9, 88+/-11 and 89+/-7 ng/l at a glycemia of 3.6 mmol/l in MODY3 patients, patients with NIDDM and controls respectively (NS). Suppression of endogenous glucose production by insulin was blunted in MODY3 patients (3.3+/-1.2 micromol/kg per min) and in patients with NIDDM (4.4+/-0.6 micromol/kg per min) compared with controls (1.7+/-0.5 micromol/kg per min, P<0.05 compared with both MODY3 patients and patients with NIDDM). During hypoglycemia, endogenous glucose production increased to 8.6+/-2.1, 8.8+/-0.7 and 7.0+/-1.0 micromol/kg per min in MODY3 patients, patients with NIDDM and controls respectively (all NS). These data indicate that mutations of HNF-1alpha in MODY3 do not result in a decreased glucagon secretion or alterations of glucose production during hypoglycemia.

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Endogenous glucose production after sequential meals in humans: evidence for more prolonged suppression after ingestion of a second meal

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00233.2018 ◽

2018 ◽

Vol 315 (5) ◽

pp. E904-E911 ◽

Cited By ~ 1

Author(s):

Teddy Ang ◽

Greg M. Kowalski ◽

Clinton R. Bruce

Keyword(s):

Real Life ◽

Glucose Production ◽

Endogenous Glucose Production ◽

Eating Patterns ◽

Plasma Glucagon ◽

Healthy Individuals ◽

Carbohydrate Ingestion ◽

Single Meal ◽

Endogenous Glucose ◽

Insulin Responses

Single-meal studies have shown that carbohydrate ingestion causes rapid and persistent suppression of endogenous glucose production (EGP). However, little is known about the regulation of EGP under real-life eating patterns in which multiple carbohydrate-containing meals are consumed throughout the day. Therefore, we aimed to characterize the regulation of EGP in response to sequential meals, specifically during the breakfast-lunch transition. Nine healthy individuals (5 men, 4 women; 32 ± 2 yr; 25.0 ± 1.4 kg/m2) ingested two identical mixed meals, each containing 25 g of glucose, separated by 4 h, and EGP was determined by the variable infusion tracer-clamp approach. EGP was rapidly suppressed after both meals, with the pattern and magnitude of suppression being similar over the initial 75-min postmeal period. However, EGP suppression was more transient after breakfast compared with lunch, with EGP returning to basal rates 3 h after breakfast. In contrast, EGP remained in a suppressed state for the entire 4-h postlunch period. This occurred despite each meal eliciting similar plasma glucose and insulin responses. However, there was greater suppression of plasma glucagon levels after lunch, likely contributing to this response. These findings highlight the potential for distinct regulation of EGP with each meal of the day and suggest that EGP may be in a suppressed state for much of the day, since EGP did not return to basal rates even after a lunch meal containing a modest amount of carbohydrate.

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