Effects of differing insulin levels on response to equivalent hypoglycemia in conscious dogs

Abstract

The aim of this study was to determine if differing concentrations of insulin can modify the counterregulatory response to equivalent hypoglycemia. Insulin was infused intraportally into normal 18-h-fasted conscious dogs at 2 (low, n = 6) or 8 mU.kg-1.min-1 (high, n = 7) on separate occasions. This resulted in steady-state arterial insulin levels of 80 +/- 8 and 610 +/- 55 microU/ml, respectively. Glucose was infused during the high dose to maintain plasma glucose similar to low (50 +/- 1 mg/dl). Despite similar plasma glucose levels, epinephrine (2,589 +/- 260, 806 +/- 180 pg/ml), norepinephrine (535 +/- 60, 303 +/- 55 pg/ml), cortisol (12.1 +/- 1.5, 5.8 +/- 1.2 micrograms/dl), and pancreatic polypeptide (1,198 +/- 150, 598 +/- 250 pg/ml) were all increased in the presence of high-dose insulin (P < 0.05). Glucagon levels were similar during both insulin infusions. Hepatic glucose production, measured with [3-3H]-glucose, rose from 2.6 +/- 0.2 to 4.7 +/- 0.3 mg.kg-1.min-1 in response to high insulin (P < 0.01) but remained unchanged, 3.0 +/- 0.5 mg.kg-1.min-1, during low-dose infusions. Six hyperinsulinemic euglycemic control experiments (2 or 8 mU.kg-1.min-1, n = 3 in each) provided baseline data. By the final hour of the high-dose euglycemic clamps, cortisol (2.4 +/- 0.4 to 4.8 +/- 0.8 micrograms/dl) and norepinephrine (125 +/- 34 to 278 +/- 60 pg/ml) had increased (P < 0.05) compared with baseline. Plasma epinephrine levels remained unchanged during both series of euglycemic studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Key Role for AMP-Activated Protein Kinase in the Ventromedial Hypothalamus in Regulating Counterregulatory Hormone Responses to Acute Hypoglycemia

“…However, because VMH-shAMPK significantly suppressed the CRR in the present study, any confounding effect of this difference is likely to have been small and, if anything, would have acted against the effect of AMPK downregulation. Moreover, insulin levels between groups in the present study differed by a much smaller amount than in previous studies (45,46,49). Thus, overall it seems unlikely that insulin per se has contributed to the findings in this study.…”

α- and β-Cell Responses to Small Changes in Plasma Glucose in the Conscious Dog

“…Because the arterial plasma glucagon level and glucagon secretion decreased so little (if at all) in response to hyperglycemia, it is evident that hyperglycemia per se, even in the presence of modestly increased plasma insulin, had little effect on basal glucagon secretion. On the other hand, a decrease in plasma glucose from 5.8 to 5.2 mmol/l triggered a significant increase in arterial glucagon and glucagon secretion (>200% of basal) at a plasma glucose value well above the well-recognized threshold of 3.8 mmol/l observed in the presence of insulin-induced hypoglycemia in humans (1,12,25,32,33) and dogs (2)(3)(4)15). However, because basal plasma glucose levels in overnight-fasted humans (~4.7 mmol/l) (1-6) are usually lower than those in overnightfasted dogs (~5.8 mmol/l), the extent of the decrease in plasma glucose required to initiate an increase in glucagon secretion in the present study (0.6 mmol/l) was only about half (~1.2 mmol/l) of that reported to initiate glucagon release in response to insulin-induced hypoglycemia in humans (1,25).…”

“…Furthermore, insulin has been postulated to exert a paracrine influence on glucagon secretion when its release is modified in response to changes in the plasma glucose concentration. To date, studies have not provided a complete understanding of the relationship between a decrement in the plasma glucose level and glucagon or insulin secretion, because the insulin level itself has been elevated to decrease the glucose level, and insulin per se can affect not only its own secretion (1), but also the release of other counterregulatory hormones, including glucagon (2)(3)(4)(5)(6)(7)(8)(9)(10)(11). Hyperinsulinemia, when paired with euglycemia, is known to increase the plasma concentrations of cortisol (5,6) and norepinephrine (7,8), but to decrease the plasma glucagon level (3,5,9).…”

“…This decrease is thought to occur via a direct inhibitory effect on the ␣-cell (10,11). In addition, Davis et al (2,12) showed that elevation of plasma insulin increases the sympatho-adrenal response to hypoglycemia in dogs and humans. The use of exogenous insulin to lower plasma glucose, therefore, does not permit assessment of the effects of a decrease in plasma glucose per se, in the absence of hyperinsulinemia, on pancreatic hormone secretion.…”

“…At least 16 days before an experiment, a laparotomy was performed under general endotrachial anesthesia (15 mg/kg body wt pentothal sodium presurgery and 1.0% isoflurane as an inhalation anesthetic during surgery), and catheters were placed into a femoral artery, the portal, a hepatic, a jejunal, and a splenic vein for blood sampling, as previously described (2)(3)(4)7,14,15). On the day of the experiment, the catheters were exteriorized under local anesthesia (2% lidocaine; Abbott, North Chicago, IL), their contents were aspirated, and they were flushed with saline.…”