Non-classical rapid effects of glucocorticoids on the beta cell function in response to glucose in healthy men
Greisa VilaMichael KrebsSabina Baumgartner‐ParzerMichaela RiedlMartin ClodiGiovanni PaciniAnton Luger
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Abstract Objective : Insulin resistance is observed in individuals with normal glucose tolerance. This indicates that increased insulin secretion can compensate for insulin resistance and that additional defects are involved in impaired glucose tolerance or type 2 diabetes. The objective of this study was to evaluate a procedure aimed at assessing the compensatory mechanisms to insulin resistance. Research Methods and Procedures : Eight healthy nonobese female patients were studied on two occasions, before and after administration of 2 mg/d dexamethasone for 2 days during a two‐step hyperglycemic clamp. Insulin secretion was assessed from plasma insulin concentrations. Insulin sensitivity was assessed from the ratio of whole‐body glucose use (6, 6 2 H 2 glucose) to plasma insulin concentrations. This procedure is known to induce a reversible impairment of glucose tolerance and insulin resistance. Results : In all subjects, dexamethasone induced a decrease in insulin sensitivity and a proportionate increase in first‐phase insulin secretion and in insulin concentrations at both steps of glycemia. The resulting hyperinsulinemia allowed the restoration of normal whole‐body glucose uptake and the suppression of plasma free fatty acids and triglycerides. In contrast, the suppression of endogenous glucose production was impaired after dexamethasone ( p < 0.01). Discussion : Increased insulin secretion fully compensates dexamethasone‐induced insulin resistance in skeletal muscle and adipose tissue but not in the liver. This suggests that failure to overcome hepatic insulin resistance can impair glucose tolerance. The compensatory insulin secretion in response to insulin resistance can be assessed by means of a hyperglycemic clamp after a dexamethasone challenge.
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Abstract. Beta-cell function, as evaluated from plasma C-peptide measurements, is found in all insulin dependent diabetic patients the first months of disease and in about 15% of patients with more than 15 years of treatment. The beta-cells are capable of modulating their secretory activity in response to changes in blood glucose. Even a minimal residual insulin secretion is of metabolic significance. Key words: insulin dependent diabetes mellitus, beta-cell function, C-peptide metabolic control.
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The hypothalamic neuropeptide oxytocin not only modulates psychosocial function, but also contributes to metabolic regulation. We have recently shown that intranasal oxytocin acutely improves beta‐cell responsivity and glucose tolerance in normal‐weight men. In the present experiment, we investigated the acute glucoregulatory impact of oxytocin in obese men with impaired insulin sensitivity. Fifteen obese healthy men with an average body mass index of 35 kg/m 2 and an average body fat content of 33% received a single intranasal dose (24 IU) of oxytocin before undergoing an oral glucose tolerance test. Results were analysed according to the oral minimal model and compared with our findings in normal‐weight participants. In contrast to the results in normal‐weight subjects, oxytocin did not blunt postprandial glucose and insulin excursions in obese men, and moreover failed to enhance beta‐cell responsivity and glucose tolerance. These results indicate that pronounced obesity may be associated with a certain degree of resistance to the glucoregulatory impact of exogenous oxytocin, and underlines the need for further investigations into the potential of oxytocin to improve glucose homeostasis in the clinical context.
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ABSTRACT. Two β‐blocking agents, non‐selective propranolol and β 1 ‐selective metoprolol, were investigated with respect to their effects on glucose metabolism in 10 hypertensive patients with non‐insulin dependent diabetes mellitus (NIDDM). The patients were treated randomly for two weeks in a double‐blind cross‐over manner with ( a ) propranolol, ( b ) metoprolol, and ( c ) placebo. Propranolol impaired glucose tolerance when compared to placebo. The increase in blood glucose was associated neither with changes in concentrations of serum insulin, plasma glucagon of free fatty acid nor with alterations in peripheral insulin sensitivity as measured by 125 I‐insulin binding to mononuclear leukocytes. Although metoprolol had no effect on blood glucose, it increased 125 I‐insulin binding to mononuclear leukocytes. The increase in insulin binding could contribute to blood glucose control during metoprolol treatment. In search for reasons for poor metabolic control in NIDDM, treatment with non‐selective β‐blockers should be kept in mind.
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Patients with overt Type 2 diabetes consistently have alterations in insulin secretion, including reduced insulin secretory responses to glucose, delayed and blunted meal-induced insulin secretion, increased pro-insulin and abnormal insulin secretory oscillations. More recently, it has become evident that abnormal insulin secretion antedates the onset of overt hyperglycaemia and is present in people with impaired glucose tolerance, i.e. normal fasting glucose and glycohaemoglobin concentrations. These defects are subtle and include shifts to the right in the dose-response curves that relate to glucose and insulin secretion, reduced ability of the β-cell to detect and respond to oscillatory changes in the plasma glucose concentration and impaired β-cell compensation for insulin resistance. In order to define the factors responsible for these defects in secretion, we have infused human patients with a lipid emulsion and heparin to raise plasma free fatty acid concentrations. This is associated with reduced ability of the β-cell to detect and respond to small changes in the plasma glucose concentration. In summary, defects in insulin secretion are consistently present in patients with impaired glucose tolerance and play a critical role in the progression from impaired glucose tolerance to diabetes.
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In addition to its pivotal role in psychosocial behavior, the hypothalamic neuropeptide oxytocin contributes to metabolic control by suppressing eating behavior. Its involvement in glucose homeostasis is less clear, although pilot experiments suggest that oxytocin improves glucose homeostasis. We assessed the effect of intranasal oxytocin (24 IU) administered to 29 healthy, fasted male subjects on glucose homeostasis measured by means of an oral glucose tolerance test. Parameters of glucose metabolism were analyzed according to the oral minimal model. Oxytocin attenuated the peak excursion of plasma glucose and augmented the early increases in insulin and C-peptide concentrations in response to the glucose challenge, while slightly blunting insulin and C-peptide peaks. Oral minimal model analyses revealed that oxytocin compared with placebo induced a pronounced increase in β-cell responsivity (PHItotal) that was largely due to an enhanced dynamic response (PHId), and a more than twofold improvement in glucose tolerance (disposition index). Adrenocorticotropic hormone (ACTH), cortisol, glucagon, and nonesterified fatty acid (NEFA) concentrations were not or were only marginally affected. These results indicate that oxytocin plays a significant role in the acute regulation of glucose metabolism in healthy humans and render the oxytocin system a potential target of antidiabetic treatment.
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The exact physiological basis of acute growth hormone (GH) suppression by oral glucose is not fully understood. Glucose-mediated increase in hypothalamic somatostatin seems to be the most plausible explanation. Attempts to better understand its underlying mechanisms are compromised by species disparities in the response of GH to glucose load. While in humans, glucose inhibits GH release, the acute elevation of circulating glucose levels in rats has either no effect on GH secretion or may be stimulatory. Likewise, chronic hyperglycemia alters GH release in both humans and rats nonetheless in opposite directions. Several factors influence nadir GH concentrations including, age, gender, body mass index, pubertal age, and the type of assay used. Besides the classical suppressive effects of glucose on GH release, a paradoxical GH increase to oral glucose may be observed in around one third of patients with acromegaly as well as in various other disorders. Though its pathophysiology is poorly characterized, an altered interplay between somatostatin and GH-releasing hormone has been suggested and a link with pituitary ectopic expression of glucose-dependent insulinotropic polypeptide receptor has been recently demonstrated. A better understanding of the dynamics mediating GH response to glucose may allow a more optimal use of the OGTT as a diagnostic tool in various conditions, especially acromegaly.
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Endogenous insulin secretion is suppressed during hyperinsulinemic euglycemic clamp, which is known as a feedback inhibition of insulin secretion (FI-IS) by insulin. Since FI-IS is impaired in obese subjects, inadequate FI-IS may partly contribute to enhanced insulin secretion seen in obesity with insulin resistance. However, significance of FI-IS in non-obese healthy subjects is unknown. To clarify the significance, we studied 49 non-obese healthy Japanese men. We evaluated steady state serum C-peptide (SSSC) and muscle insulin sensitivity (MIS) by hyperinsulinemic euglycemic clamp with tracer (insulin infusion rate = 20 mU/m2 per min). We also measured intrahepatic lipid (IHL) by 1H-MRS. Based on the median of SSSC, we divided the subjects into low FI-IS group and high FI-IS group and compared clinical parameters. While fasting C-peptide level was comparable between the groups, the SSSC was suppressed by 50% from baseline in the high FI-IS group (1.14±0.39 to 0.57±0.24 ng/ml, p<0.001), but less suppressed in the low FI-IS group (1.34±0.34 to 1.19±0.24 ng/ml, p=0.054). Although most of metabolic parameters such as fasting glucose, lipid levels and visceral fat volume were comparable between the groups, low FI-IS group showed IHL accumulation (3.0±4.2 vs. 0.6±0.2%, p=0.04) and impaired MIS (0.19±0.04 vs. 0.28±0.08 mg/kg FFM・min-1・μU-1・ml, p<0.001), compared with high FI-IS group. Consistently, we observed elevated AUC of insulin during 75 g-OGTT in low FI-IS group (6.6±3.0 vs. 3.9±2.0 μU・min/ml・103, p=0.001), while AUC of glucose was comparable. In conclusion, even in healthy non-obese men, subjects with inadequate FI-IS were existed and those were characterized by impaired MIS and hyperinsulinemia during OGTT. These data suggested that impaired FI-IS may be early change to maintain metabolic status through enhancing insulin secretion in the face of moderate muscle insulin resistance in healthy non-obese men.
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