Hyperglucagonemia precedes a decline in insulin secretion and causes hyperglycemia in chronically glucose-infused rats

Abstract

GI, Kibbey RG. Hyperglucagonemia precedes a decline in insulin secretion and causes hyperglycemia in chronically glucose-infused rats. Am J Physiol Endocrinol Metab 301: E1174 -E1183, 2011. First published August 23, 2011; doi:10.1152/ajpendo.00175.2011.-Islet damage from glucose toxicity is implicated in the pathogenesis of type 2 diabetes, but the sequence of events leading to islet cell dysfunction and hyperglycemia remains unclear. To examine the early stages of islet pathology resulting from increased basal glucose loads, normal awake rats were infused with glucose continuously for 10 days. Plasma glucose and markers of islet and liver function were monitored throughout the infusion. After initial hyperglycemia, rats adapted to the infusion and maintained euglycemia for approximately 4 days. Continued infusion led to worsening hyperglycemia in just 5% of rats after 6 days, but 69% after 8 days and 89% after 10 days, despite unchanged basal and stimulated plasma insulin and C-peptide concentrations. In contrast, plasma glucagon concentrations increased fivefold. Endogenous glucose production (EGP) was appropriately suppressed after 4 days (2.8 Ϯ 0.7 vs. 6.1 Ϯ 0.4 mg·kg Ϫ1 ·min Ϫ1 on day 0, P Ͻ 0.001) but tripled between days 4 and 8 (9.9 Ϯ 1.7 mg·kg Ϫ1 ·min Ϫ1 , P Ͻ 0.01). Surprisingly, the increase in EGP was accompanied by increased mitochondrial phosphoenolpyruvate carboxykinase expression with appropriate suppression of the cytosolic isoform. Infusion of anti-glucagon antibodies normalized plasma glucose to levels identical to those on day 4 and ϳ300 mg/dl lower than controls. This improved glycemia was associated with a 60% reduction in EGP. These data support the novel concept that glucose toxicity may first manifest as ␣-cell dysfunction prior to any measurable deficit in insulin secretion. Such hyperglucagonemia could lead to excessive glucose production overwhelming the capacity of the ␤-cell to maintain glucose homeostasis. glucagon; hepatic glucose production; type 2 diabetes THE MECHANISMS THAT UNDERLIE THE EARLY STAGES of the progression to type 2 diabetes (T2D) are not fully understood. Inappropriately elevated endogenous glucose production (EGP) derived primarily from increased gluconeogenesis associated with hyperglucagonemia is an early feature in the progression to diabetes (16,27,28). Unlike the periodic and interrupted nature of prandial contributions to plasma glucose, EGP uniquely can contribute continuously to the glucose pool. Consequently, the sustained increase in insulin secretion throughout the day required to dispose of the increased EGP will increase the "basal workload" of islet cells. Although the mechanism is unclear, hyperglucagonemia has also been well documented in patients (2, 31, 33) and animal models (17,19,35,38) of diabetes with both hyper-and hypoinsulinemia, and it contributes to hyperglycemia by augmenting EGP. Because of the multiple physiological abnormalities in diabetic patients and most animal models, it is difficult to determine the relative contribution of h...

Glucagon receptor antibody completely suppresses type 1 diabetes phenotype without insulin by disrupting a novel diabetogenic pathway

“…In 1974, it was reported that hyperglycemia paradoxically stimulates glucagon secretion in dogs with chemically induced diabetes (10). More recently, plasma glucagon concentrations were reported to rise, with a tripling of hepatic glucose production, in normal rats continuously infused with glucose at a constant rate (11). Thus, there is evidence that in the absence of adequate insulin, elevated glucose might stimulate glucagon production, which in turn aggravates hyperglycemia.…”

Metabolic manifestations of insulin deficiency do not occur without glucagon action

“…The elegant studies of Jamison et al (39) provide strong tangible support for this theory. As recently reviewed, the α-cell defect in that disorder consists of failure to suppress glucagon during influx of nutrients because of defective paracrine signaling from β-cells (38).…”

A Role for Mitochondrial Phosphoenolpyruvate Carboxykinase (PEPCK-M) in the Regulation of Hepatic Gluconeogenesis

“…At the end of the studies, rats were anesthetized with intravenous pentobarbital, and tissues were freeze-clamped and stored at Ϫ80°C for later analysis of hepatic glycogen, triglycerides, and mRNA (15,21,22). To minimize disturbance, rats were swivel-harnessed for the fasting studies and had free access to the cage (15). Glucose turnover rates were determined by primed continuous infusion of 99% D- [6,6-D 2 ]glucose (21,22).…”

“…PEPCK-M lacks the strong transcriptional regulation that is characteristic of PEPCK-C (9). An exception is in the chronically glucose-infused rat where augmented PEPCK-M expression accommodates the pathogenic increase in gluconeogenesis (15). The importance of PEPCK-C to human diabetes has recently come under additional scrutiny because PEPCK-C mRNA, protein, and activity from liver biopsy of humans with type 2 diabetes do not correlate with EGP (16).…”