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Diabetes acutely impairs the ability of the liver to synthesize glycogen. However, the effect of chronic diabetes on the glycogenic function of the liver is not known. We measured hepatic glycogen contents in streptozotocin (STZ)-diabetic rats 3 weeks or 9 months after the induction of diabetes, in the fed state and following a 24-hour fast. In the fed state, liver glycogen levels were markedly decreased in short-term diabetic animals (5.8 +/- 2.0 v 33.9 +/- 2.3 mg/g, P less than .001), but not in long-term diabetic rats (18.3 +/- 4.4 v 20.7 +/- 1.3 mg/g, P = NS) as compared with age-matched nondiabetic animals, despite comparable hyperglycemia (portal plasma glucose levels of 424 +/- 21 and 449 +/- 24 mg/100 mL, short- and long-term diabetics, respectively). In the fasted state, on the other hand, liver glycogen was depleted in acute diabetes (4.5 +/- 2.2 mg/g v 1.9 +/- 0.5 of control rats), but significantly increased in chronic diabetes (10.1 +/- 3.1 v 0.2 +/- 0.03 mg/g, P less than .001). The latter finding was confirmed by electron-microscopical examination of liver cells. Furthermore, the percentage of hepatic glycogen synthase in the active form (synthase a) was lower than normal in short-term diabetic rats and in old nondiabetic rats. In long-term diabetic animals, on the other hand, synthase a was significantly higher than in old controls (P less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin-mediated glucose metabolism (euglycemic insulin clamp at plasma insulin concentration of 100 microU/mL) and glucose-stimulated insulin secretion (hyperglycemic clamp) were examined in 42 obese subjects (ideal body weight [IBW], 158 +/- 4%) with normal glucose tolerance and in 36 normal weight (IBW, 102% +/- 1%) age-matched controls. In 10 obese and eight control subjects, insulin was infused at six rates to increase plasma insulin concentration by approximately 10, 20, 40, 80, 2,000, and 20,000 microU/mL. Throughout the physiologic range of plasma insulin concentrations, both the increase in total body glucose uptake and the suppression of hepatic glucose production (HGP) were significantly impaired in the obese group (P less than .001 to .01). At the two highest plasma insulin concentrations, inhibition of HGP and the stimulation of glucose disposal were similar in both the obese and control groups. Insulin secretion during the hyperglycemic (+/- 125 mg/dL) clamp was twofold greater in obese subjects than in controls (P less than .01) and was inversely related to the rate of glucose uptake during the insulin clamp (r = -.438, P less than .05), but was still unable to normalize glucose disposal (P less than .05). In conclusion, our results indicate that insulin resistance is a common accompaniment of obesity and can be overcome at supraphysiological insulin concentrations. Both in the basal state and following a hyperglycemic stimulus obese people display hyperinsulinemia, which correlates with the degree of insulin resistance. However, endogenous hyperinsulinemia fails to fully compensate for the insulin resistance.

It has been suggested that raised levels of parathyroid hormone (PTH) may induce glucose intolerance and impair insulin action in primary as well as secondary hyperparathyroidism. Furthermore, PTH is known to stimulate glycogenolysis in isolated hepatocytes and renal cortical cells. We administered a bolus of bovine 1:84 PTH to 8 awake dogs, and measured hepatic glucose production by the primed-constant 3H-3-Glucose infusion technique for 2 hr. PTH injection had no effect on fasting plasma glucose concentration or hepatic glucose production. Plasma insulin and glucagon, serum ionized and total calcium, and serum phosphate did not show any significant change following PTH administration. Synthetic bovine 1:34 PTH, administered to another 3 dogs using the same experimental protocol, also failed to affect any of the measured parameters. To investigate the possible synergism between PTH and other glycoactive hormones, we infused glucagon (3 ng/min · kg, 5 dogs) or epinephrine (0.1 ng/min · kg, 6 dogs) with or without 1:84 PTH in matched experiments. Glucagon alone caused a 22% rise (p < 0.01) in plasma glucose concentration and a 27% rise (p < 0.05) in hepatic glucose production; epinephrine alone induced a 54% rise (p < 0.01) in plasma glucose and a 39% increase (p < 0.01) in glucose production. When PTH injection was combined with glucagon or epinephrine infusion, no further stimulation of hepatic glucose production was observed. In another 6 awake dogs with portal and hepatic venous and arterial catheters, the hepatic response to PTH was determined both by measuring net hepatic glucose balance (hepatic plasma flow times transhepatic glucose concentration difference) and by tracer methodology. While the two techniques showed excellent agreement, both failed to show any effect of PTH. Four dogs in this group received 1:84 PTH obtained from commercial source. In all the other studies here reported, 1:84 PTH prepared in our laboratory was used. Both preparations caused a marked rise in phosphate excretion in dogs, and had the same potency as standard synthetic bovine 1:34 PTH in stimulating c-AMP generation by isolated renal tubular membranes. We conclude that the acute administration of PTH does not stimulate hepatic glucose production in the dog.

In order to express in equivalent terms seemingly divergent results obtained with isotopic tracer studies as compared to hepatic venous catheter studies on the role of the liver in the metabolism of oral glucose, our previously published studies using the hepatic venous catheter technique in normals and diabetics given intravenous and/or oral glucose were analyzed with respect to the splanchnic fractional extraction of glucose, total splanchnic glucose influx, and the proportion of total glucose metabolism accounted for by net splanchnic glucose uptake. In normal subjects during extreme hyperinsulinemia (plasma insulin, 500–1,200 μU/ml) induced by i.v. insulin while maintaining the blood glucose concentration at basal levels (insulin clamp), total glucose metabolism rose to 10.5 ± 0.9 mg/min · kg, while splanchnic fractional extraction of glucose was 4.2 ± 1.1%, and net splanchnic glucose uptake accounted for only 5 ± 2% of total glucose turnover. During hyperglycemic (blood glucose, 200 mg/dl) hyperinsulinemia induced by i.v. glucose, net splanchnic glucose uptake was twice that observed with euglycemic hyperinsulinemia, and the proportion of total glucose metabolism occurring in the splanchnic bed rose to 14 ± 4%. These increments were due entirely to a rise in splanchnic glucose influx since the fractional extraction (3.4 ± 0.5%) remained unchanged from that observed with euglycemic hyperinsulinemia. After oral glucose (100 g), splanchnic glucose influx was comparable to hyperglycemic hyperinsulinemia induced with i.v. glucose, but splanchnic fractional extraction rose to 13.1 ± 1.9% (p < 0.001 versus i.v. glucose), a value comparable to that observed with isotopic studies of oral glucose metabolism. Total glucose turnover was, however, 30% lower than after i.v. insulin (p < 0.01), so that net splanchnic glucose uptake accounted for 54 ± 5% of total glucose metabolism. In maturity-onset diabetics, after 100 g oral glucose splanchnic glucose influx was 69% greater than in controls (p < 0.001), but net splanchnic glucose uptake was 44% below controls (2.3 ± 0.5 versus 4.1 ± 0.5 mg/min · kg, p < 0.02). This reduction in glucose uptake could be accounted for by a splanchnic fractional extraction ratio (4.7 ± 1.4%) that was 64% lower than in controls given oral glucose (p < 0.001). It is concluded that: (1) in normal subjects, the ability of the splanchnic area to extract circulating glucose (as reflected by the splanchnic fractional extraction) is 2–3-fold greater after oral glucose than after intravenous glucose; (2) the rise in splanchnic fractional extraction to levels of 13% in association with only moderate increases in total glucose turnover fully accounts for the predominance of the splanchnic area in the metabolism of oral as compared to intravenous glucose; and (3) in maturity-onset diabetics, oral glucose fails to induce a rise in splanchnic fractional extraction of glucose comparable to that observed in normal subjects.