M. J. Christopher

Multiple defects of both hepatic and peripheral intracellular glucose processing contribute to the hyperglycaemia of NIDDM

SummaryNon-insulin-dependent diabetic (NIDDM) patients were studied during a modified euglycaemic state when fasting hyperglycaemia was normalized by a prior (−210 to −150 min) — and later withdrawn (−150–0 min) — intravenous insulin infusion. Glucose metabolism was assessed in NIDDM patients (n=10) and matched control subjects (n=10) using tritiated glucose turnover rates, indirect calorimetry and skeletal muscle glycogen synthase activity determinations. Total and non-oxidative exogenous glycolytic flux rates were measured using appearance rates of tritiated water. A+180 min euglycaemic hyperinsulinaemic (40 mU·m−2·min−1) clamp was performed to determine the insulin responsiveness of the various metabolic pathways. Plasma glucose concentration increased spontaneously during baseline measurements in the NIDDM patients (−120 to 0 min: 4.8±0.3 to 7.0±0.3 mmol/l; p<0.01), and was primarily due to an elevated rate of hepatic glucose production (3.16±0.13 vs 2.51±0.16 mg·kg FFM−1·min−1; p<0.01). In the NIDDM subjects baseline glucose oxidation was decreased (0.92±0.17 vs 1.33±0.14 mg·kg FFM−1·min−1; p<0.01) in the presence of a normal rate of total exogenous glycolytic flux and skeletal muscle glycogen synthase activity. The simultaneous finding of an increased lipid oxidation rate (1.95±0.13 vs 1.61±0.07 mg·kg FFM−1·min−1; p=0.05) and increased plasma lactate concentrations (0.86±0.05 vs 0.66±0.03 mmol/l; p=0.01) are consistent with a role for both the glucose-fatty acid cycle and the Cori cycle in the maintenance and development of fasting hyperglycaemia in NIDDM during decompensation. Insulin resistance was demonstrated during the hyperinsulinaemic clamp in the NIDDM patients with a decrease in the major peripheral pathways of intracellular glucose metabolism (oxidation, storage and muscle glycogen synthase activity), but not in the pathway of non-oxidative glycolytic flux which was not completely suppressed during insulin infusion in the NIDDM patients (0.55±0.15 mg·kg FFM−1·min−1; p<0.05 vs 0; control subjects: 0.17±0.29; NS vs 0). Thus, these data also indicate that the defect(s) of peripheral (skeletal muscle) glucose processing in NIDDM goes beyond the site of glucose transport across the cell membrane.

Insulin secretion in growth hormone—deficient adults: Effects of 24 months' therapy and five days' acute withdrawal of recombinant human growth hormone

Beta-cell function in growth hormone (GH)-deficient (GHD) adults is poorly documented. Beta-cell function was therefore studied in 10 GHD adults (age, 40+/-3 years; weight, 79.3+/-4.8 kg; body mass index [BMI], 27.5+/-1.3 kg x m(-2)) before and after 6- and 24-month recombinant human GH (rhGH) therapy (0.24 IU x kg(-1) x wk(-1)) compared with 10 age-, sex-, weight-, and BMI-matched control subjects. With rhGH therapy, fat-free mass (FFM) increased (48.2+/-4.9, 52.5+/-4.8, and 59+/-6.8 kg, respectively) and fat mass (FM) decreased (33.8%+/-2.8%, 28.0%+/-3.0%, and 29.4%+/-2.5%, respectively), as did serum cholesterol. Oral glucose tolerance initially deteriorated at 6 months, but improved toward the control value by 24 months. Fasting insulin (FI) increased significantly, as did the acute insulin response to oral glucose (deltaAIR(OGTT)/deltaG) at 30 minutes (FI: pretreatment 9.8+/-0.8, 6 months, 14.0+/-1.8, 24 months 12.5+/-1.6 v control 11.4+/-1.9 mU x L(-1); deltaAIR(OGTT)/deltaG: pretreatment 201+/-24, 6 months 356+/-41, 24 months 382+/-86 v control 280+/-47 mU x mmol(-1)). However, the acute insulin response to intravenous (IV) glucose (AIR(G)) and IV glucagon at euglycemia and hyperglycemia did not change with rhGH therapy and were similar to the control group values. Importantly, the expected reciprocal relationships (as observed for the control group) between the various insulin secretory parameters and insulin sensitivity (SI) either were not present or were statistically weak in GHD subjects, despite the 35% decrease in SI by 24 months of rhGH therapy. In particular, over time, there was an attenuation of insulin secretion with respect to the ongoing insulin resistance with rhGH therapy, particularly for AIR(G) at 24 months. After 5 days of rhGH withdrawal, insulin secretion decreased and SI improved in GHD subjects. It is concluded that the current long-term rhGH treatment regimens appear to impact on insulin secretion such that the normal relationships between insulin secretion and SI are altered despite the favorable impact on body composition and serum lipid profiles.

Contrasting action of short- and long-term adrenaline infusion on dog skeletal muscle glucose metabolism

SummaryThere are important differences between the short- and long-term effects of adrenaline on determinants of glucose tolerance. To assess this metabolic adaptation at tissue level, the present study examined the effect of acute and prolonged in vivo elevation of adrenaline on glycogen metabolism and glycolysis in skeletal muscle. Adrenaline (50 ng · kg−1 · min−1) was infused for 2 h or 74 h and the results compared with 1 h 0.9% NaCl infusion in six trained dogs. Muscle glycogen content was reduced by long-term adrenaline (161 ± 17 vs NaCl 250 ± 24 μmol/g dry weight;p < 0.05) but not short-term adrenaline (233 ± 21) indicating a sustained effect of adrenaline on glycogen metabolism. Acutely, glycogen synthase I was reduced (short-term adrenaline 12 ± 6 vs NaC122 ± 7μmol glycosyl units · g−1 · min−1;p < 0.05) but returned to normal with prolonged adrenaline infusion (20 ± 5). In contrast, Km for glycogen phosphorylasea was not changed acutely (short-term adrenaline 31 ± 6 vs NaCl 27 ± 7 mmol/1 inorganic phosphate) but was reduced during long-term infusion (19 ± 4;p < 0.05 vs short-term adrenaline). Thus, with short- and long-term adrenaline infusion, there were different enzyme changes, although likely to promote glycogenolysis in both cases. In the glycolytic pathway the substrates glucose 6-phosphate and fructose 6-phosphate did not change significantly and hexokinase was not inhibited. Acutely, phosphofructokinase had reduced Vmax (short-term adrenaline 34 ± 6 vs NaCl 44 ± 5 U/g; p < 0.05) but was still above the maximal operating rate in vivo. With prolonged adrenaline infusion, the Km for phosphofructokinase was reduced (long-term adrenaline 0.32 ± 0.03 vs NaCl 0.44 ± 0.07 mmol/l fructose 6-phosphate;p < 0.05). In this situation of relatively low glycolytic flux, the sustained glycogenolytic effect of prolonged adrenaline infusion mediated by increased glycogen phosphorylase a ctivity occurs without a significant accumulation of hexose monophosphates or impairment of glycolysis.

Effects of Acute and Chronic Counterregulatory Hormone Infusions on Glucose Tolerance and Insulin Sensitivity in Diabetic Dogs

The effects of elevated EPI and CORT levels on KG, SI and SG were studied in dogs with alloxan-induced diabetes. Conscious dogs received SAL, EPI 20 ng μ kg−1 · min−1 for 30 min (short EPI) or 72 h (long EPI), or CORT 200 μg · kg−1 · min−1 for 60 min (short CORT) or 72 h (long CORT) before assessment of glucose metabolism by rapid sampling for glucose and insulin levels after 300 mg/kg i.v. glucose and exogenous insulin infusion designed to simulate the normal secretory pattern. With EPI infusion, KQ fell acutely from 2.9 ± 0.4 to 2.0 ± 0.2%/min (SAL vs. short EPI, P < 0.05), but rose to 3.4 ± 0.4%/min during long EPI. Minimal-model analysis of the glucose response with the insulin data as input showed that S1 decreased acutely from 4.7 ± 1.8 to 2.5 ± 0.6 × 10−5 min−1/pM (SAL vs. short EPI, P < 0.05), but rose to 4.5 ± 2.5 × 10−1 min−1/pM during long EPI. The effects of EPI on SG paralleled the results for KG and S1, with acute decline from 3.9 ± 0.4 to 2.1 ± 0.4 × 10−2 min−1 (SAL vs. short EPI, P < 0.05) and recovery to 3.3 ± 0.3 × 10−2 min−1 during long EPI. During CORT infusion, Kg tended to fall (SAL 2.9 ± 0.4 vs. short CORT 2.5 ± 0.5 vs. long CORT 2.2 ± 0.5%/min). This decline was related to a fall of S1 (SAL 4.7 ±1.8 vs. short CORT 2.7 ± 1.8 vs. long CORT 1.2 ± 0.7 × 10−1 min−1/pM, P < 0.05 long CORT vs. SAL), whereas SG levels were similar for the three groups. These results indicate that, in the absence of any compensatory change of insulin secretion, adaptation to the metabolic effects of long-term hormone elevation occurs for EPI but not CORT, which has a sustained effect on S1. Therefore, CORT may be more important than EPI as a contributor to long-term stress-induced hyperglycemia in people with type I diabetes.

The relationship between peripheral glucose utilisation and insulin sensitivity in the regulation of hepatic glucose production: studies in normal and alloxan-diabetic dogs

Hepatic glucose overproduction (HGP) of diabetes could be primary or could occur in response to the metabolic needs of peripheral (skeletal muscle (SkM)) tissues. This question was tested in normal and diabetic dogs.