Role of Hepatic Glycogen Breakdown in Defective Counterregulation of Hypoglycemia in Intensively Treated Type 1 Diabetes

Abstract

Impairment of hypoglycemic counterregulation in intensively treated type 1 diabetes has been attributed to deficits in counterregulatory hormone secretion. However, because the liver plays a critical part in recovery of plasma glucose, abnormalities in hepatic glycogen metabolism per se could also play an important role. We quantified the contribution of net hepatic glycogenolysis during insulininduced hypoglycemia in 10 nondiabetic subjects and 7 type 1 diabetic subjects (HbA 1c 6.5 ؎ 0.2%) using 13 C nuclear magnetic resonance spectroscopy, during 2 h of either hyperinsulinemic euglycemia (plasma glucose 92 ؎ 4 mg/dl) or hypoglycemia (plasma glucose 58 ؎ 3 mg/dl). In nondiabetic subjects, hypoglycemia was associated with a brisk counterregulatory hormone response (plasma epinephrine 246 ؎ 38 vs. 2,785 ؎ 601 pmol/l during hypoglycemia, plasma norepinephrine 1.9 ؎ 0.2 vs. 2.5 ؎ 0.3 nmol/l, and glucagon 38 ؎ 7 vs. 92 ؎ 17 pg/ml, respectively, P < 0.001 in all), and a relative increase in endogenous glucose production (EGP 0.83 ؎ 0.14 mg ⅐ kg ؊1 ⅐ min ؊1 during euglycemia yet ϳ50% higher with hypoglycemia [1.30 ؎ 0.20 mg ⅐ kg ؊1 ⅐ min ؊1 ], P < 0.001). Net hepatic glycogen content declined progressively during hypoglycemia to 22 ؎ 3% below baseline (P < 0.024). By the final 30 min of hypoglycemia, hepatic glycogen fell from 301 ؎ 14 to 234 ؎ 10 mmol/l (P < 0.001) and accounted for ϳ100% of EGP. In marked contrast, after an overnight fast, hepatic glycogen concentration in type 1 diabetic subjects (215 ؎ 23 mmol/l) was significantly lower than in nondiabetic subjects (316 ؎ 19 mmol/l, P < 0.001). Furthermore, the counterregulatory response to hypoglycemia was significantly reduced with small increments in plasma epinephrine and norepinephrine (126 ؎ 22 vs. 448 ؎ 16 pmol/l in hypoglycemia and 0.9 ؎ 0.3 vs. 1.6 ؎ 0.3 nmol/l, respectively, P < 0.05 for both) and no increase in plasma glucagon. EGP decreased during hypoglycemia with no recovery (1.3 ؎ 0.5 vs.

Hyperinsulinaemia during exercise does not suppress hepatic glycogen concentrations in patients with type 1 diabetes: a magnetic resonance spectroscopy study

“…It is plausible that a preserved exercise-induced increase in circulating catecholamines rather than the glucagon response enabled continuous substrate mobilisation from the liver in this patient cohort [14,30,[36][37][38]. It is known that pre-exercise hypoglycaemia is associated with blunted counter-regulation and impaired hepatic glycogenolysis [23,39]. Since in the present study, patients were admitted overnight and hypoglycaemia was avoided prior to the experiment, counter-regulatory mechanisms were likely to have been preserved.…”

“…Human studies using magnetic resonance spectroscopy (MRS) have reported defects in mobilisation of hepatic glycogen stores in patients with type 1 diabetes [23,24]. However, these studies were performed either under very low circulating insulin concentrations (30-60 pmol/l) or after hypoglycaemia.…”

Noninvasive evaluation of liver repopulation by transplanted hepatocytes using31P MRS imaging in mice

“…A multislice gradient echo imaging sequence was used for scout images (flip ϭ 45°, TR ϭ 0.8 s, TE ϭ 10 ms, FOV ϭ 32 or 48 mm 2 , slice thickness ϭ 2 mm). 31 P MRSI data were acquired using a 90°nonselective adiabatic hypersecant excitation pulse. Spectroscopic images were generated with a three-dimensional phase-encoding scheme using spherical sampling on a 13 ϫ 13 ϫ 13 grid (FOV ϭ 32 or 48 mm 2 , TR ϭ 0.4-0.6 s, 2 transients) with a total acquisition time of 30-40 minutes.…”

“…2A displays a scout image and indicates regions of interest for the three 31 P magnetic resonance spectra shown in a study of the CK-Tg mice. PCr resonance was seen in each liver region of interest, indi- 31 P MRS spectra of CK-Tg mouse liver. CK-Tg mice were fed a liquid diet fortified with 10% creatine monohydrate for 4 days.…”

Hepatic Steatosis in Type 1 Diabetes

“…In intensively treated type 1 diabetes patients, hypoglycemia failed to stimulate hepatic glycogen breakdown or activation of endogenous glucose production, despite activation of counterregulation. According to the authors, these factors may contribute to the defective hypoglycemic counterregulation seen in type 1 diabetes patients [102].…”