To elucidate the potency of continuous vs. intermittent exposure to hormonal stimuli, hepatic glucose production of isolated perfused rat livers was monitored in response to glucagon and insulin infusion. Using a nonrecirculating perfusion system, continuous exposure to glucagon (35 pM) induced a rise in hepatic glucose production from basal 0.33 +/- 0.03 mmol/(96 min X 100 g BW) to 0.65 +/- 0.02 mmol/(96 min X 100 g BW), while intermittent exposure (3 min on/off intervals; total dose 50%) to the same glucagon concentration elicited an almost identical rise in hepatic glucose production to 0.59 +/- 0.12 mmol/(96 in X 100 g BW). Insulin (100 mU/liter) given continuously and intermittently (3 min on/off intervals) inhibited glucagon-stimulated (70 pM) hepatic glucose production to the same extent, i.e. by 37.4% and 41.1%, respectively. Doubling the off period to 6 min and thereby reducing the total hormone dose to 33% did not diminish insulin's suppressive effect on glucagon-stimulated hepatic glucose release (34.6%). When the latter infusion protocol was applied with insulin at 300 mU/liter, hepatic glucose production during the first 40 min of glucagon infusion was more restrained (P less than 0.01) than during continuous delivery of 100 mU/liter, although the same amount of insulin was infused per period of time. In parallel, glucagon-stimulated cAMP release was similarly suppressed by insulin in all experiments. From this we conclude that the effect on hepatic glucose production of pulsatile administration of glucagon as well as of insulin, depending on the applied time interval of hormone exposure, is equipotent or even superior to the respective hormones' continuous infusion even if the hormone load is significantly reduced.
To evaluate the role of pulsatile insulin administration, hepatic glucose production (HGP) and utilization were studied in type I diabetic patients in the fasting state and during a euglycemic insulin (1 mU X kg-1 X min-1 i.v.) clamp with continuous and pulsatile insulin administration. In the latter study, insulin was infused at twice the continuous rate with 3-min-on/7-min-off intervals, thereby reducing total insulin delivery by 40%. The restraining effect of pulsatile insulin on basal HGP (1.91 +/- 0.35 mg X kg-1 X min-1) was equipotent to continuous insulin exposure (1.80 +/- 0.17 mg X kg-1 X min-1). During the insulin-clamp studies, HGP was equally suppressed by pulsed (0.62 +/- 0.12 mg X kg-1 X min-1) as by continuous insulin infusion (0.63 +/- 0.12 mg X kg-1 X min-1). Insulin-stimulated glucose utilization was not significantly altered in either study (2.55 +/- 0.27 vs. 2.92 +/- 0.23 mg X kg-1 X min-1). When in further studies the total insulin dose given during the pulsatile study was infused continuously (0.6 mU X kg-1 X min-1), HGP in the basal state and residual HGP during the insulin-clamp study were 25-30% higher than in the pulsatile experiments, whereas glucose utilization was not significantly different. In conclusion, by reducing total hormone delivery by up to 40%, but given in a pulsatile fashion, insulin is equally potent in controlling HGP as continuous insulin administration. This greater efficacy of pulsatile exposure in suppressing HGP is accompanied by an equipotent effect on glucose utilization.(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of acetyl-salicylic acid (ASA, 3 g per day for 3 days) on glucose utilization and insulin secretion was studied in healthy volunteers and Type 2 diabetic patients using the hyperglycaemic and euglycaemic insulin clamp technique. When in healthy subjects arterial plasma glucose was acutely raised and maintained at +7 mmol/l above fasting level, the plasma insulin response was enhanced by ASA (70 +/- 7 vs. 52 +/- 7 mU/l), whereas the plasma C-peptide response was identical. Despite higher insulin concentrations, glucose utilization was not significantly altered (control, 61 +/- 7; ASA, 65 +/- 6 mumol X kg-1 X min-1) indicating impairment of tissue sensitivity to insulin by ASA. Inhibition of prostaglandin synthesis was not likely to be involved in the effect of ASA, since insulin response and glucose utilization were unchanged following treatment with indomethacin. In the euglycaemic insulin (1 mU X kg-1 X min-1) clamp studies, glucose utilization was unaltered by ASA despite higher insulin concentrations achieved during constant insulin infusion (103 +/- 4 vs. 89 +/- 4 mU/l). In Type 2 diabetic patients, fasting hyperglycaemia (10.6 +/- 1.1 mmol/l) and hepatic glucose production (15 +/- 2 mumol X kg-1 X min-1) fell upon ASA treatment (8.6 +/- 0.7 mmol/l; 13 +/- 1 mumol X kg-1 X min-1). During the hyperglycaemic clamp study, the plasma response of insulin, but not of C-peptide, was enhanced by ASA, whereas tissue sensitivity to insulin was reduced by 30 percent.(ABSTRACT TRUNCATED AT 250 WORDS)
To understand better impairment of glucose utilization in diabetics during a hyperosmolal state, in vitro models were established to evaluate the effects of hyperosmolality on basal glucose uptake as well as glucagon dependent glucose release by isolated hepatocytes. In these studies simulating a hyperglycaemic (40 mmol glucose) and hyperosmolal (up to 500 mosm kg-1, NaCl as added solute) state basal hepatic glucose uptake was reversibly suppressed by 19% when osmolality was increased by as little as 10 mosm kg-1. No such effects on glucose uptake by isolated hepatocytes could be attained when the incubation's fluid osmolality was augmented by the addition of urea or mannitol. Estimations of the transport rates of 3-O-methylglucose and uptake of 2-deoxyglucose at 400 vs. 300 mosm kg-1 revealed that impaired intracellular enzymatic activity but not the transport rate of glucose into the cell were responsible for the hyperosmolal defect as uptake was more reduced (P less than 0.025) by increased osmolality for 2-deoxyglucose (16%) than for 3-O-methylglucose (13%). Glucagon dependent glucose release from isolated hepatocytes was diminished by 17.8% when the osmolality was raised to 400 mosm kg-1 by NaCl as added solute. These data obtained in vitro support the clinical contention that a hyperosmolal state, which corresponds to a loss of fluid in excess of solutes, is able to impair basal hepatic glucose uptake as well as glycogenolytic glucagon action on the liver.
Hyperthyroidism is known to further impair carbohydrate metabolism in diabetic patients. In the present study we examined in noninsulin-dependent (type 2) diabetic patients the effect of T3-induced hyperthyroidism on glucose utilization and endogenous glucose production by means of the hyperinsulinemic and hyperglycemic clamp technique in combination with [3H]3-glucose kinetic analysis. Administration of T3 for 1 week increased the mean serum T3 concentration from 1.0 +/- 0.1 (SEM) to 4.1 +/- 0.2 ng/ml, and the mean fasting plasma glucose from 8.7 +/- 0.7 to 9.9 +/- 0.9 mmol/liter. Basal hepatic glucose production (HGP) rose from 3.23 +/- 0.23 to 3.98 +/- 0.25 mg/kg X min, whereas basal MCR of glucose (MCRG) increased only slightly from 2.12 +/- 0.24 to 2.30 +/- 0.14 ml/kg X min. When the plasma insulin concentration was acutely raised and maintained at 82 +/- 8 microU/ml (hyperinsulinemic clamp study), HGP decreased to 0.71 +/- 0.29 mg/kg X min and MCRG increased to 3.16 +/- 0.47 ml/kg X min. After T3 administration suppression of HGP by insulin was reduced (1.55 +/- 0.37 mg/kg X min), but at the same time MCRG was only slightly affected (3.64 +/- 0.54 ml/kg X min). In the hyperglycemic clamp study the plasma glucose concentration was maintained 7 mmol/liter above the individual fasting level. MCRG was again slightly higher after T3 administration (1.98 +/- 0.18 vs. 1.66 +/- 0.15 ml/kg X min), but insufficient to completely compensate for the higher residual HGP at the hyperthyroid as compared to the euthyroid state (2.42 +/- 0.24 vs. 1.45 +/- 0.36 mg/kg X min). Thus, deterioration of metabolic control in noninsulin-dependent diabetic patients by hyperthyroidism is due primarily to enhancement of basal HGP and its reduced suppressibility by insulin and glucose.
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