Reduced Plasma Insulin Levels Research Articles

Effects of Exercise and Diet on Weight Gain During Nicotine Cessation in Rats1

The present experiment examined the effects of exercise and the prevention of access to sweet food on nicotine cessation‐induced changes in body weight, body fat, and plasma insulin levels in rats. As in previous studies, nicotine administration reduced body weight gain and sweet food consumption, and nicotine cessation increased body weight gain and sweet food consumption. Exercise (swimming) reduced nicotine cessation‐induced increases in weight gain and body fat, and reduced plasma insulin levels. Preventing access to sweet food also reduces plasma insulin levels and body fat, but did not reduce weight gain. Insulin sensitivity is discussed as a possible mechanism for changes in body weight resulting from nicotine administration and cessation. In addition, the possible implications of these findings for behavioral and pharmacological interventions to prevent weight gain induced by smoking cessation are presented.

In vivo metformin treatment ameliorates insulin resistance: evidence for potentiation of insulin-induced translocation and increased functional activity of glucose transporters in obese (fa/fa) Zucker rat adipocytes.

To examine the cellular mechanism of the antihyperglycemic action of in vivo metformin (M) we used an animal model of severe insulin resistance, the genetically obese (fa/fa) Zucker rat. The animals were treated with or without M (250 mg/kg.day) which was supplied with the drinking water. Three weeks of in vivo M-treatment had no effect on body weight and several blood lipid parameters, but markedly reduced plasma insulin levels by 45% (-M: 2932 +/- 166 vs. +M: 1614 +/- 85 pmol/liter, P < 0.01); plasma glucose was slightly but significantly decreased by 8.3% (-M: 7.2 +/- 0.2 vs. +M: 6.6 +/- 0.16 mmol/liter, P < 0.05). Adipocytes were isolated and incubated with or without insulin. In vivo M-treatment had no effect on basal 3-O-methylglucose uptake. In contrast, in vivo M-treatment increased insulin-stimulated glucose transport by 2.6 +/- 0.6-fold (P < 0.01). Measurement of cell surface insulin receptors revealed no effect of M on neither specific [125I]insulin binding nor on insulin receptor kinase activity. Insulin-mediated translocation of both GLUT1 and GLUT4 glucose transporters was enhanced by in vivo M-treatment, GLUT1 by 26.1%, GLUT4 by 30.5%. To fully account for the M-induced increment of insulin-stimulated glucose transport (2.6-fold), these data suggest that M increased the functional activity of glucose transporters. We conclude that amelioration of insulin resistance in (fa/fa) Zucker rats after 3 weeks of in vivo M-treatment is associated with 1) a marked reduction of in vivo hyperinsulinemia, 2) an increase of insulin-stimulated glucose transport in adipocytes; 3) this increase of insulin-stimulated glucose transport is accompanied with both a potentiation of insulin-induced translocation of GLUT1 and GLUT4 glucose transporters from an intracellular pool to the plasma membrane as well as increased functional activity of plasma membrane glucose transporters. 4) This M-effect seems to be independent of de novo glucose transporter synthesis, since total cellular GLUT1 and GLUT4 glucose transporter number were uneffected by M. 5) These results strongly suggest a direct action of M at the level of glucose transport, since neither tracer insulin binding nor insulin receptor kinase activity were significantly altered by M.

Effects of ciglitazone on blood pressure and intracellular calcium metabolism.

Ciglitazone is the prototype of the thiazolidinedione class of compounds currently being developed for the treatment of insulin resistance and non-insulin-dependent diabetes. The effects of thiazolidinediones on blood pressure and cell calcium metabolism are not well defined. In the obese Zucker rat, a widely studied model of insulin resistance associated with mild hypertension, we investigated the effects of ciglitazone on plasma insulin levels and mean arterial pressure. We also evaluated the effects of ciglitazone on the changes in cytosolic calcium induced by platelet-derived growth factor in A172 human glioblastoma cells and rat A10 vascular smooth muscle cells. Oral administration of ciglitazone, approximately 45 mg/kg per day for 4 weeks, induced significant reductions in plasma insulin levels (p < 0.001) and blood pressure (p < 0.05). Ciglitazone was also found to significantly attenuate the capacity of platelet-derived growth factor BB homodimer to induce sustained increases in intracellular free calcium. These findings suggest that thiazolidinediones may offer a novel pharmacological approach to the treatment of hypertension, and raise the possibility that these compounds may affect blood pressure not only by affecting insulin metabolism but also by modifying the cell calcium response to pressor agents, growth factors, or both.

Dietary carbohydrate utilization in cod (Gadus morhua): metabolic responses to feeding and fasting

Moist diets with increasing amounts of carbohydrate (0.5%, 10% and 21% on a dry weight basis) were each fed to duplicate groups of cod (initial weight 370 g) for 8 weeks, after which all groups were fasted for 4 weeks. Protein energy was high and accounted for more than 70% of the gross energy content in all feeds, and the diets were maintained isocaloric by substituting lipid energy for carbohydrate energy. No indigestible binder was added. Excellent growth and feed conversion were obtained in all groups. After 4 weeks of fasting, fish previously fed diets with either 10% or 21% carbohydrate showed significantly higher weight loss than fish fed the diet without carbohydrate. Liver glycogen reached 10% of liver wet weight in fish fed diets containing 10% or 21% carbohydrate and 5% in fish receiving 0.5% carbohydrate after 8 weeks. Following 4 weeks of fasting, liver glycogen was reduced to similar levels in all fish. Plasma glucose levels 4 h after feeding were higher in fish fed the diets with 10% or 21% carbohydrate and plasma free amino acid levels (FAA) were lower, than in fish fed the diet containing 0.5% carbohydrate. Blood lactate concentrations were unaffected during the first 24 h after feeding. After 4 weeks of food deprivation, the levels were significantly reduced only in the 21% carbohydrate group. A link between glucagon and protein metabolism is suggested because plasma glucagon concentration followed the same pattern as the concentrations of plasma FAA throughout the study. Insulin and glucagon-like peptide (GLP) showed a covariation throughout the experiment. Reduced plasma insulin levels were seen after fasting concomitant with reduction in the levels of FAA and glucose. It is suggested that insulin secretion in cod is affected both by plasma FAA and glucose and that cod meets food deprivation by slowing down metabolism.

Effects of antihypertensive therapy on insulin resistance.

In view of the likely prohypertensive effects of hyperinsulinemia and the presence of insulin resistance in primary hypertension, the effects of various antihypertensive therapies on insulin sensitivity need to be identified. The evidence strongly supports major beneficial effects of weight reduction and aerobic exercise. Deleterious effects have been shown for diuretics and most beta-blockers, whereas probable beneficial effects have been seen with alpha-blockers, one angiotensin converting enzyme inhibitor, and various calcium entry blockers. Improvement of insulin sensitivity and reduction of plasma insulin levels are desirable attributes of antihypertensive therapy that should be more carefully considered in the future.

Diabetes induced in male transgenic mice by expression of human H-ras oncoprotein in pancreatic beta cells.

Transgenic mice expressing an insulin-promoted H-ras hybrid gene in pancreatic beta cells developed beta-cell degeneration and diabetes. The disease was manifested in male mice by hyperglycemia, glycosuria, and reduced plasma insulin levels, which appeared around 5 months of age and led to premature death. Histological analyses revealed large holes within the islets of Langerhans and a reduced number of beta cells. The destruction of the islets was not associated with an obvious inflammatory activity. Ultrastructural analysis showed extensive engorgement in the endoplasmic reticulum of the residual beta cells from diabetic males. The females carrying the insulin-promoted ras gene did not manifest any of the physiological abnormalities observed in males and showed only minor histological and ultrastructural changes, even at much greater ages.

Diabetes Induced in Male Transgenic Mice by Expression of Human H-ras Oncoprotein in Pancreatic β Cells

Transgenic mice expressing an insulin-promoted H-ras hybrid gene in pancreatic beta cells developed beta-cell degeneration and diabetes. The disease was manifested in male mice by hyperglycemia, glycosuria, and reduced plasma insulin levels, which appeared around 5 months of age and led to premature death. Histological analyses revealed large holes within the islets of Langerhans and a reduced number of beta cells. The destruction of the islets was not associated with an obvious inflammatory activity. Ultrastructural analysis showed extensive engorgement in the endoplasmic reticulum of the residual beta cells from diabetic males. The females carrying the insulin-promoted ras gene did not manifest any of the physiological abnormalities observed in males and showed only minor histological and ultrastructural changes, even at much greater ages.

Circulating levels of insulin and avian pancreatic polypeptide in pigeons under different experimental conditions

Changes in circulating levels of insulin and avian pancreatic polypeptide (APP) were studied in pigeons under different experimental conditions. Anesthetized pigeons in which the pectoralis muscles were stimulated electrically for periods of 1 or 5 hr showed significant reduction in plasma insulin levels but not in APP levels. Cold exposure (−15°, 90 min) of fully feathered (FF) or partially (dorsum and breast) defeathered (PD) pigeons produced no significant changes in plasma levels of insulin or APP. Heat exposure (+45°, 90 min) of FF and PD pigeons caused no change in plasma levels of insulin; however, APP levels were significantly increased. In pigeons subjected to bilateral cervical vagotomy, there was no change in the level of plasma insulin but APP levels were found to be significantly increased.

Beta endorphin modulation of the glucoregulatory effects of repeated epinephrine infusion in alloxan-diabetic and normal dogs.

When repeated epinephrine infusions are given to normal dogs as a partial stress model, there is exaggerated hyperglycaemia, associated with reduced plasma insulin levels and markedly decreased glucose clearance. In the present study, we have examined the hormonal and metabolic responses to two successive 60-min epinephrine (0.1 microgram . kg-1 . min-1) infusions with or without concomitant infusion of beta endorphin (0.3 microgram . kg-1 . min-1) in 6 alloxan-diabetic dogs. These studies have been compared to similar studies in 5 normal dogs. In the diabetic dogs, plasma glucose rose from 12.3 +/- 2.2 to 16.2 +/- 2.4 mmol/l (p less than 0.001) in response to the first epinephrine infusion and rose further to 18.1 +/- 2.5 mmol/l (p less than 0.001) during the second epinephrine infusion. The increases in plasma glucagon and glucose production were comparable with both infusions, but considerably greater than previously observed in normal dogs. In normal dogs, beta endorphin diminished the insulin response to the first epinephrine infusion (p less than 0.02), and abolished this response to the second (p less than 0.05). In addition beta endorphin also diminished the glucagon response to the second epinephrine infusion (p less than 0.01) and greatly potentiated epinephrine-induced suppression of glucose metabolic clearance during both infusions (p less than 0.001). However, beta endorphin did not appreciably alter the hyperglycaemic response to epinephrine due to a concomitant attenuation of the epinephrine-induced increase in hepatic glucose production. In contrast to normal dogs, beta endorphin did not modulate the effects of either the first or second epinephrine infusion on glucose kinetics in diabetic dogs. Also, beta endorphin failed to inhibit glucagon or insulin secretion in response to epinephrine in the diabetic animals. Since the alloxan-diabetic and normal dogs respond differently to the combined infusion of beta endorphin and epinephrine we conclude that the effects of beta endorphin observed in the normal dogs are dependent upon intact pancreatic endocrine function.

The antiobesity action of (S)-(+)-1-(4-chlorophenylthiomethyl)-N-methylethylamine fumarate (AO-124)

The antiobesity effects of (S)-(+)-1-(4-chlorophenylthiomethyl)-N-methylethylamine fumarate (AO-124) were examined in rats and dogs. AO-124 suppressed food intake dose dependently in normal, Zucker fatty and VMH-obese rats, and beagle dogs. Its anorectic activity was not altered by pretreatment with methysergide, a serotonin receptor blocker. AO-124 also reduced the hyperphagia induced by 2-deoxy-D-glucose but not that induced by insulin, noradrenaline or muscimol, suggesting that the anoretic mechanism of AO-124 may be implicated in a glucostatic regulatory system of feeding. In addition, AO-124 decreased insulin secretion in response to an oral, but not an intravenous, glucose load. Such a suppression in insulin secretion may be explained by slow absorption of glucose from the intestine: AO-124 delayed the gastric emptying time of glucose and inhibited the active transport of glucose as observed in the everted small intestine. Two week administration of AO-124 to Zucker fatty rats resulted in a significant reduction of plasma insulin levels, body weight gain, and body lipid without exerting any changes in body protein. These findings indicate that AO-124 may be useful as an antiobesity agent on the basis of its unique mechanisms of action.

Studies of the human liver insulin receptor in noninsulin-dependent diabetes mellitus.

The insulin binding characteristics and the structural components of the insulin receptor were studied in the purified liver plasma membranes from seven patients with noninsulin-dependent diabetes (NIDDM) and seven control subjects. In comparison to the controls, diabetic subjects had a 65% reduction in plasma insulin levels in response to an oral glucose load. Specific insulin binding by liver membranes from diabetic patients was, however, twofold greater than the binding activity by membranes from control subjects. This alteration resulted largely from an increase in the number of insulin receptors and a modest increase in receptor binding affinity. Holo (nonreduced) receptor species of similar molecular weights were detected by an affinity labeling technique in the two membrane preparations and sulfhydryl reduction demonstrated an insulin binding subunit of 125,000 mol wt. Overall, these results show that the hepatic insulin resistance of NIDDM cannot be explained by a deficiency in insulin binding.

Inhibition of lipid accumulation and enhancement of energy expenditure by the addition of pyruvate and dihydroxyacetone to a rat diet

To assess the effects of oral intake of pyruvate and dihydroxyacetone on body composition and metabolism, rats were divided into two groups and pair-fed one of the following isocaloric diets for 112 days. The control diet was a liquid diet with the following caloric composition: 14% protein, 28% fat, and 58% carbohydrate. The experimental diet was the same as the control diet except for the partial substitution of carbohydrate content with pyruvate and dihydroxyacetone. Rats receiving the experimental diet gained less weight than rats receiving the control diet. This reduction in body weight appeared to be largely the result of inhibition of lipid accumulation. The experimental diet reduced body fat content by 32% without any significant effect on either protein or water content. Rats receiving the experimental diet did not have increased loss of calories in the stool, but had greater rates of heat production and energy expenditure, which was accompanied by an elevated plasma level of thyroxine. Furthermore, rats receiving the experimental diet had a smaller rate of lipid synthesis in their adipose tissue, and a reduced plasma insulin level. The data suggest that inhibition of gain in weight with the addition of pyruvate and dihydroxyacetone to the diet is the result of an increased loss of calories as heat at the expense of storage as lipid.

Modulation of basal insulin secretion in the obese, hyperglycemic mouse

The modulation of basal insulin secretion in vivo in the obese hyperglycemic, hyperinsulinemic ob ob mouse was investigated by recording the plasma insulin and glucose levels during 2 hr after administration of various insulin secretory modifiers assumed to interfere with different regulatory mechanisms for insulin release. Normal, lean NMRI mice served as controls. Glucose sensitive mechanisms were tested by studying the effects of mannoheptulose. It was observed that mannoheptulose induced a marked hyperglycemia of comparable magnitude in both obese and lean mice. However, it exerted a more profound and sustained inhibitory effect on insulin secretion in the obese mouse than in the lean control animals, suppressing the insulinogenic index by 85%–90% in the obese animals from 30 min and onwards. Autonomic regulation was studied by means of receptor blockade. β-Adrenoceptor blockade by l-propranolol transiently inhibited basal insulin secretion in both obese and lean animals by a maximum of about 40%, the depression in obese animals being somewhat more sustained. Further, in both types of mice, α-adrenoceptor blockade by phentolamine induced a sustained elevation of plasma insulin levels to about 200% over control values. Thus no impressive abnormality in the adrenergic regulation of insulin secretion in the obese mouse was detected. Cholinergic blockade by methylatropine was found to induce a pronounced and sustained reduction of plasma insulin levels of about 60% in the obese mouse whereas the lean mice exhibited only a slight and transitory depression. The islet hormone, pancreatic polypeptide (PP) was observed to induce a slight short-lasting depression, about 35%, of basal insulin levels in both obese and lean mice concomitant with a slight reduction in plasma glucose levels. Vinblastine, in a dose known to induce a 75% reduction of the amount of microtubules in the insulin cells, was found to depress basal insulin secretion in the obese mouse by about 60% from 30 min and onwards, whereas only a slight slow-onset depression of about 25% was noted in the lean mouse. A slight hyperglycemia was noted in lean but not in obese mice. It is concluded that the basal hypersecretion of insulin in the obese mouse is of multifactorial origin. Fully established it probably is largely governed by an increased sensitivity and reactivity to glucose stimulation and to an enhanced responsiveness to a normal and/or increased vagal activity.