Cortisol-Induced Insulin Resistance in Man: Impaired Suppression of Glucose Production and Stimulation of Glucose Utilization due to a Postreceptor Defect of Insulin Action*

Short-term growth hormone excess is associated with impaired hepatic and extrahepatic responses to insulin in the absence of a change in insulin binding. To determine whether similar defects occur after chronic growth hormone excess, insulin dose-response curves for stimulation of glucose utilization and suppression of glucose production and monocyte and erythrocyte insulin binding were determined in five acromegalic patients and six healthy volunteers of comparable age, sex, and obesity. During infusion of insulin, glucose infusion rates required to maintain euglycemia were significantly lower (P less than 0.02 all) in the acromegalic patients than in the control subjects. Suppression of glucose production was impaired in the acromegalic subjects at insulin concentrations in the physiological range but not at insulin concentrations in the supraphysiological range. In contrast stimulation of glucose utilization was decreased in the acromegalic subjects at both physiological and supraphysiological insulin concentrations. Neither monocyte nor erythrocyte insulin binding differed significantly in the acromegalic and control subjects. These data indicate that chronic growth hormone excess is associated with a defect in both hepatic and extrahepatic insulin action. The decrease in glucose utilization at supraphysiological insulin concentrations in the acromegalic subjects and the normal monocyte and erythrocyte insulin binding suggest a postbinding alteration in insulin action.

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Metformin improves peripheral but not hepatic insulin action in obese patients with type II diabetes

Acta Endocrinologica ◽

10.1530/acta.0.1200257 ◽

1989 ◽

Vol 120 (3) ◽

pp. 257-265 ◽

Cited By ~ 71

Author(s):

Ole Hother-Nielsen ◽

Ole Schmitz ◽

Per H. Andersen ◽

Henning Beck-Nielsen ◽

Oluf Pedersen

Keyword(s):

Type Ii Diabetes ◽

Insulin Action ◽

Glucose Utilization ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Metformin Treatment ◽

Obese Patients ◽

Type Ii ◽

Plasma Lactate ◽

Hepatic Glucose

Abstract. Nine obese patients with Type II diabetes mellitus were examined in a double-blind cross-over study. Metformin 0.5 g trice daily or placebo were given for 4 weeks. At the end of each period fasting and day-time postprandial values of plasma glucose, insulin, C-peptide and lactate were determined, and in vivo insulin action was assessed using the euglycemic clamp in combination with [3-3H]glucose tracer technique. Metformin treatment significantly reduced mean day-time plasma glucose levels (10.2 ± 1.2 vs 11.4 ± 1.2 mmol/l, P< 0.01) without enhancing mean day-time plasma insulin (43 ± 4 vs 50 ± 7 mU/l, NS) or C-peptide levels (1.26 ± 0.12 vs 1.38 ± 0.18 nmol/l, NS). Fasting plasma lactate was unchanged (1.57 ± 0.16 vs 1.44 ± 0.11 mmol/l, NS), whereas mean day-time plasma lactate concentrations were slightly increased (1.78 ± 0.11 vs 1.38 ± 0.11 mmol/l, P< 0.01). The clamp study revealed that metformin treatment was associated with an enhanced insulin-mediated glucose utilization (370 ± 38 vs 313 ± 33 mg · m−2 · min−1, P< 0.01), whereas insulin-mediated suppression of hepatic glucose production was unchanged. Also basal glucose clearance was improved (61.0 ± 5.8 vs 50.6 ± 2.8 ml · n−2 · min−1,, P< 0.05), whereas basal hepatic glucose production was unchanged (81 ± 6 vs 77 ± 4 mg · m−2 · min−1, NS). Conclusions: 1) Metformin treatment in obese Type II diabetic patients reduces hyperglycemia without changing the insulin secretion. 2) The improved glycemic control during metformin treatment was associated with an enhanced insulin-mediated glucose utilization, presumably in skeletal muscle, whereas no effect could be demonstrated on hepatic glucose production.

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Temporal changes in insulin resistance and secretion in 24-h-fasted conscious pregnant rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1993.265.6.e845 ◽

1993 ◽

Vol 265 (6) ◽

pp. E845-E851 ◽

Cited By ~ 11

Author(s):

G. Rossi ◽

R. S. Sherwin ◽

A. S. Penzias ◽

P. Lapaczewski ◽

R. J. Jacob ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Action ◽

Insulin Dose ◽

Glucose Production ◽

Late Pregnancy ◽

Hepatic Insulin Resistance ◽

Pregnant Rats ◽

Hyperglycemic Clamp ◽

Peripheral Insulin Resistance ◽

Insulin Responses

To determine the temporal sequence of pregnancy-induced changes in insulin action and secretion, awake midpregnant (11-12 days) and late pregnant (19-20 days) rats underwent a two-step euglycemic hyperinsulinemic or a hyperglycemic clamp study after a 24-h fast. During euglycemia, insulin-stimulated increments in glucose uptake and clearance in midpregnant rats were reduced by 60-70% at the lower dose (insulin approximately 360 pM) and by 20-30% at the higher dose (insulin approximately 1,750 pM; P < 0.01 vs. virgin controls). Insulin action was also diminished in late pregnant rats. However, the magnitude of resistance did not increase. Insulin-mediated suppression of glucose production was only minimally impaired in midpregnancy. In contrast, glucose production was virtually unchanged in late pregnancy, even at the highest insulin dose. During hyperglycemia, insulin responses in late pregnancy were markedly increased 5-fold above controls and 2.5-fold above midpregnant rats (P < 0.05). We conclude that rat pregnancy is characterized by the early appearance of peripheral insulin resistance. As pregnancy progresses toward term, marked hepatic insulin resistance and insulin hypersecretion develop, whereas peripheral insulin resistance demonstrates negligible changes. These data imply that insulin hypersecretion during late pregnancy is most closely linked to hepatic insulin resistance, at least in 24-h-fasted animals.

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Insulin resistance in the GK rat: decreased receptor number but normal kinase activity in liver

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1993.265.5.e807 ◽

1993 ◽

Vol 265 (5) ◽

pp. E807-E813 ◽

Cited By ~ 14

Author(s):

S. Bisbis ◽

D. Bailbe ◽

M. A. Tormo ◽

F. Picarel-Blanchot ◽

M. Derouet ◽

...

Keyword(s):

Insulin Resistance ◽

Glucose Utilization ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Gk Rat ◽

Peripheral Tissues ◽

Relative Index ◽

Gk Rats ◽

Euglycemic Clamp

We have previously shown that the glucose intolerance and the hyperglycemic state in the GK rat, a new spontaneous model of non-insulin-dependent (type II) diabetes without obesity, are partly accounted for by an alteration of the pancreatic B cell response. On the other hand, the hyperglycemic-hyperinsulinemic pattern in these rats suggests a decrease of response to insulin in the basal state. In the present study, in vivo insulin action was assessed in 8-wk-old GK females at basal and submaximal (euglycemic clamp) insulin levels. Overall glucose utilization (OGU), individual tissue glucose utilization (ITGU, in vivo uptake of the glucose analogue 2-deoxy-D-glucose as the relative index of glucose metabolism), as well as hepatic glucose production (GP) and liver insulin receptor properties were determined under these two conditions. The basal OGU was significantly higher in the GK females, compared with that in control Wistar females. The hyperinsulinemic-euglycemic clamp experiments indicated that peripheral insulin resistance was installed at 8 wk of age in the GK females because 1) OGU was significantly lower and 2) in some peripheral tissues (epitrochlearis muscle, periovarian, and inguinal white adipose tissues), but not all, ITGU was significantly lower compared with corresponding ITGU in control rats. In the basal state GP was significantly higher in the GK rats. At submaximal hyperinsulinemia (and euglycemia), it was less effectively suppressed than in the controls, thus demonstrating liver insulin resistance. Under both basal state and clamp condition, binding of 125I-A14-insulin to liver membranes of GK rats was significantly decreased by 20-30%.(ABSTRACT TRUNCATED AT 250 WORDS)

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Evaluation of in vivo insulin action and glucose metabolism in milk-fed rats

Bioscience Reports ◽

10.1007/bf01122799 ◽

1992 ◽

Vol 12 (4) ◽

pp. 273-280 ◽

Cited By ~ 1

Author(s):

M. Kergoat ◽

Ch. Gespach ◽

G. Rosselin ◽

B. Portha

Keyword(s):

Glucose Metabolism ◽

Insulin Action ◽

Glucose Utilization ◽

Glucose Production ◽

Female Rats ◽

Whole Body ◽

Utilization Rate ◽

High Fat ◽

Milk Feeding

Milk diet has long been recommended in the management of gastrointestinal pathologies. Since milk feeding represents a high fat-low carbohydrate diet and it is acknowledged that insulin resistance is one of the consequences of high fat feeding, it is important to know whether or not chronic milk feeding leads to an impairment of the insulin-mediated glucose metabolism. To examine this question, adult female rats were given raw cow's milk (50% of total calories as lipids) for 18 days. They were compared to rats raised in parallel and fed the standard laboratory diet (15% of total calories as lipids). At the end of the 18 day period, body weight, daily caloric intake, basal plasma glucose and insulin levels in the milk-fed rats were similar to those in the control rats. In vivo insulin action was assessed with the euglycemichyperinsulinemic clamp technique in anesthetized animals. These studies were coupled with the 2-deoxyglucose technique allowing a measurement of glucose utilization by individual tissues. In the milk fed rats: 1) the basal rate of endogenous glucose production was significantly (p<0.01) reduced (by 20%); 2) their hepatic glucose production was however normally suppressed by hyperinsulinemia; 3) their basal glucose utilization rate was significantly (p<0.01) reduced (by 20%); 4) their glucose utilization rate by the whole-body mass or by individual tissues was normally increased by hyperinsulinemia. These results indicate that insulin action in adult rats is not grossly altered after chronic milk-feeding, at least under the present experimental conditions.

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Experimental hyperthyroidism does not induce hepatic insulin resistance in the miniature pig

Biochemical Journal ◽

10.1042/bj2340537 ◽

1986 ◽

Vol 234 (3) ◽

pp. 537-541 ◽

Cited By ~ 7

Author(s):

M J Müller ◽

J Möring ◽

H J Seitz

Keyword(s):

Insulin Resistance ◽

Blood Glucose ◽

Insulin Action ◽

Glucose Utilization ◽

Hepatic Insulin Resistance ◽

Miniature Pig ◽

Glucose Kinetics ◽

Experimental Hyperthyroidism ◽

Arterial Concentration ◽

Glucose Output

The effect of hypo- and hyper-thyroidism on insulin-mediated alterations in tracer-determined glucose kinetics and the arterial concentration of gluconeogenic precursors were investigated in 24 h-starved conscious unrestrained miniature pigs. Hyperinsulinaemia (about 40 microunits/ml) decreased blood glucose and, transiently, glucose output at unaltered glucose utilization in all thyroid states: this effect was pronounced in hyperthyroid (-50%) and less in hypothyroid pigs (-25%) compared with euthyroid controls (-35%). We conclude that moderate experimental hyperthyroidism does not induce hepatic insulin resistance, whereas hypothyroidism slightly impairs insulin action with respect to the regulation of glucose output.

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Insulin action and glucose metabolism in sheep fed on dried-grass or ground, maize-based diets

British Journal Of Nutrition ◽

10.1079/bjn19850131 ◽

1985 ◽

Vol 54 (2) ◽

pp. 459-471 ◽

Cited By ~ 28

Author(s):

A. N. Janes ◽

T. E. C. Weekes ◽

D. G. Armstrong

Keyword(s):

Glucose Metabolism ◽

Insulin Action ◽

Plasma Insulin ◽

Glucose Utilization ◽

Glucose Production ◽

Endogenous Glucose Production ◽

Whole Body ◽

Glucose Disposal ◽

Metabolic Clearance ◽

Endogenous Glucose

1. The effect of an exogenous supply of glucose, provided by the digestion of maize starch in the small intestine, on endogenous glucose metabolism and insulin action was studied in sheep using the euglycaemic insulin clamp procedure.2. Insulin was infused intravenously at rates of 0.2, 0.5, 1.0 and 6.0 mU/min per kg live weight for four consecutive periods in each of four sheep fed on dried-grass and maize-based diets. Glucose was also infused intravenously at a variable rate, sufficient to maintain the plasma glucose concentration at basal levels. Whole-body rates of glucose metabolism were determined using a continuous infusion of [6-3H]glucose.3. From the resultinginsulin dose-response curves, it was observed that, when the sheep were fed on the dried-grass diet, the responsiveness of glucose metabolism to insulin was less than that reported for non-ruminants.4. When fed the maize-based diet, the glucose metabolic clearance rates (MCR) observed during insulin infusions were significantly greater (P < 0.05) than those observed for the dried-grass diet. However, after correcting for the non-insulin-mediated glucose disposal, differences between diets were not significant.5. The sensitivity of glucose utilization to insulin was not affected by diet. The plasma insulin concentrations causing half-maximal insulin-mediated glucose MCR were 103 (SE 21) and 85 (SE 11) mU/l for the dried-grass and maize-based diets respectively.6. The sensitivity of endogenous glucose production to insulin was also unaffected by diet. The plasma insulin concentrations resulting in the suppression of endogenous glucose production to half the basal level were 80 (SE 26) and 89 (SE 29) mU/l for the dried-grass and maize-based diets respectively.7. It is concluded that the observed increase in glucose utilization on the maize-based diet was due partly to a slight change in responsiveness to insulin and also partly to a change in the rate of non-insulin-mediated glucose disposal.

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Glucose utilization and insulin action in adult rats submitted to prolonged food restriction

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1992.263.1.e1 ◽

1992 ◽

Vol 263 (1) ◽

pp. E1-E7 ◽

Cited By ~ 15

Author(s):

F. Escriva ◽

C. Rodriguez ◽

J. Cacho ◽

C. Alvarez ◽

B. Portha ◽

...

Keyword(s):

Glucose Tolerance ◽

Insulin Action ◽

Food Restriction ◽

Glucose Utilization ◽

Glucose Production ◽

Whole Body ◽

Glucose Turnover ◽

Euglycemic Hyperinsulinemic Clamp ◽

Adult Rats ◽

Peripheral Tissues

Glucose tolerance and insulin effects on glucose production and utilization by various tissues were studied in 70-day-old anesthetized rats submitted to food restriction from the fetal stage. Basal and glucose-induced plasma insulin levels were reduced in food-restricted rats without alterations in glucose tolerance. Insulin action was quantified by using the euglycemic-hyperinsulinemic clamp technique. Glucose turnover rates were measured by using D-[6-3H]glucose. Exogenous insulin failed to decrease glucose production in food-restricted rats. Weight-related whole body glucose utilization was higher in restricted rats than in controls both in the basal (21.9 +/- 0.7 vs. 9.4 +/- 0.6 mg.min-1.kg-1) and hyperinsulinemic states (37.5 +/- 1.1 vs. 14.0 +/- 1.2 mg.min-1.kg-1). Local glucose utilization by peripheral tissues was estimated by a 2-deoxy-D-[1-3H]glucose technique. In both basal and hyperinsulinemic conditions glucose utilization was increased in various adipose and muscle tissues of the food-restricted rats as compared with the controls. Thus we conclude that food restriction leads to an increase in the insulin-mediated glucose uptake by various peripheral tissues and to insulin resistance in the liver.

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