Hyperinsulinemia Suppresses Glucose Utilization in Specific Brain Regions:<i>In Vivo</i>Studies Using the Euglycemic Clamp in the Rat

Grunstein, H. S.; James, David E.; Storlien, Leonard H; Smythe, George A.; Kraegen, Edward W.

doi:10.1210/endo-116-2-604

Cited by 67 publications

(31 citation statements)

References 47 publications

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“…This effect, however, may be dependent on the greater brain concentration of detemir insulin, which enables it to suppress brain glucose utilization (53) and, hence, cause neuroglycopenia. The higher score of neuroglycopenic symptoms with detemir compared with human insulin might be similarly interpreted.…”

Section: Discussionmentioning

confidence: 99%

Different Brain Responses to Hypoglycemia Induced by Equipotent Doses of the Long-Acting Insulin Analog Detemir and Human Regular Insulin in Humans

et al. 2008

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OBJECTIVE-The acylated long-acting insulin analog detemir is more lipophilic than human insulin and likely crosses the blood-to-brain barrier more easily than does human insulin. The aim of these studies was to assess the brain/hypothalamus responses to euglycemia and hypoglycemia in humans during intravenous infusion of equipotent doses of detemir and human insulin.RESEARCH DESIGN AND METHODS-Ten normal, nondiabetic subjects (six men, age 36Ϯ7 years, and BMI 22.9Ϯ2.6 kg/m 2 ) were studied on four occasions at random during intravenous infusion of either detemir or human insulin in euglycemia (plasma glucose 90 mg/dl) or during stepped hypoglycemia (plasma glucose 90, 78, 66, 54, and 42 mg/dl steps).RESULTS-Plasma counterregulatory hormone response to hypoglycemia did not differ between detemir and human insulin. The glycemic thresholds for adrenergic symptoms were higher with detemir (51 Ϯ 7.7 mg/dl) versus human insulin (56 Ϯ 7.8 mg/dl) (P ϭ 0.029). However, maximal responses were greater with detemir versus human insulin for adrenergic (3 Ϯ 2.5 vs. 2.4 Ϯ 1.8) and neuroglycopenic (4 Ϯ 3.9 vs. 2.7Ϯ2.5) symptoms (score, P Ͻ 0.05). Glycemic thresholds for onset of cognitive dysfunction were lower with detemir versus human insulin (51 Ϯ 8.1 vs. 47 Ϯ 3.6 mg/dl, P ϭ 0.031), and cognitive function was more deteriorated with detemir versus human insulin (P Ͻ 0.05). CONCLUSIONS-Compared with human insulin, responses tohypoglycemia with detemir resulted in higher glycemic thresholds for adrenergic symptoms and greater maximal responses for adrenergic and neuroglycopenic symptoms, with an earlier and greater impairment of cognitive function. Additional studies are needed to establish the effects of detemir on responses to hypoglycemia in subjects with diabetes. Diabetes 57:746-756, 2008 T he physiology of glucose counterregulation to hypoglycemia in humans has been extensively studied (1). A progressive decline in plasma glucose induced by insulin triggers a well-established sequence of hierarchic responses that occur at specific glycemic thresholds (2-4).It is important that new insulin formulations and/or insulin analogs available for treatment of diabetes are compared with the reference human insulin for thresholds of responses and overall responses to hypoglycemia to exclude additional risks of inducing hypoglycemia unawareness. The rapid-acting insulin analogs lispro (5) and aspart (6) and the long-acting analog glargine (7) have been shown to be no different in terms of responses to hypoglycemia versus human insulin. Regarding the longacting insulin analog detemir, there are no systematic observations with the exception of two preliminary studies-one in normal, nondiabetic subjects (8) and the other in subjects with type 1 diabetes (9)-with conflicting results.Insulin detemir is a long-acting soluble insulin analog with a 14 C fatty acid chain conferring lipophility, associated with free fatty acid (FFA) binding sites on albumin (10). Because of these characteristics, the responses of insulin detemir to hypoglycemi...

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Section: Discussionmentioning

confidence: 99%

Different Brain Responses to Hypoglycemia Induced by Equipotent Doses of the Long-Acting Insulin Analog Detemir and Human Regular Insulin in Humans

et al. 2008

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“…Insulin values above the physiological range have been shown to increase plasma catecholamines up to twofold in dogs (29) and humans (30) during hypoglycemia. High insulin in the presence of euglycemia has also been shown to increase cortisol levels (31,32). Thus, the potential effect of insulin to increase catecholamine and cortisol levels could certainly confound the interpretation of the effects of antecedent corticosterone on autonomic nervous system responses during subsequent hypoglycemia.…”

Section: Discussionmentioning

confidence: 99%

Cortisol Acts Through Central Mechanisms to Blunt Counterregulatory Responses to Hypoglycemia in Conscious Rats

et al. 2003

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Physiological levels of cortisol have been found to blunt neuroendocrine and metabolic responses to subsequent hypoglycemia in humans. The aim of this study was to determine whether cortisol acts directly on the brain to elicit this effect. A total of 41 conscious unrestrained Sprague-Dawley rats were studied during 2-day experiments. Day 1 consisted of two episodes of clamped 2-h hyperinsulinemic (30 pmol ⅐ kg ؊1 ⅐ min ؊1 ) hypoglycemia (2.8 ؎ 0.1 mmol/l; n ‫؍‬ 12; ANTE HYPO), euglycemia (6.2 ؎ 0.1 mmol/l; n ‫؍‬ 12; ANTE EUG), or euglycemia (6.2 ؎ 0.1 mmol/l) plus simultaneous intracerebroventricular (ICV) infusion of cortisol (25 g/h; n ‫؍‬ 9; ANTE EUG؉Cort) or saline (24 l/h; n ‫؍‬ 8; ANTE EUG؉Sal). For all groups, day 2 consisted of a 2-h hyperinsulinemic (30 pmol ⅐ kg ؊1 ⅐ min ؊1 ) hypoglycemic (2.9 ؎ 0.2 mmol/l) clamp. Plasma epinephrine and glucagon incremental area under the curve (⌬AUC) responses were significantly less in ANTE EUG؉Cort and ANTE HYPO versus both ANTE EUG and ANTE EUG؉Sal (P < 0.05). The ⌬AUC responses of plasma norepinephrine were significantly lower in ANTE EUG؉Cort versus both ANTE EUG and ANTE EUG؉Sal (P < 0.05). Endogenous glucose production was significantly less in ANTE HYPO and ANTE EUG؉Cort versus the other groups (P < 0.05). Lastly, the glucose infusion rate to maintain the desired hypoglycemia was significantly greater in ANTE EUG؉Cort and ANTE HYPO versus the other two groups (P < 0.05). In summary, ICV infusion of cortisol significantly blunted norepinephrine, epinephrine, glucagon, and endogenous glucose production responses to next-day hypoglycemia. We conclude that cortisol can act directly on the central nervous system to blunt counterregulatory responses to subsequent hypoglycemia in the conscious rat. Diabetes 52:2198 -2204, 2003 I ntensive glucose control in type 1 diabetic patients can slow the progression or prevent complications of diabetes such as retinopathy, nephropathy, or neuropathy (1). Unfortunately, it is also well established that intensive glucose treatment increases the frequency of severe hypoglycemia (2). The mechanism for the increased frequency of hypoglycemia may not be simply due to insulin excess. It has been clearly established (3-5) that repeated exposure to hypoglycemia can reduce neuroendocrine (catecholamine, glucagon, and growth hormone) and metabolic (endogenous glucose production [EGP], lactate, and glycerol) counterregulatory responses to subsequent hypoglycemia by as much as 50% in healthy humans and type 1 diabetic subjects (6,7). Thus, blunted counterregulatory responses make type 1 diabetic patients susceptible to an increased vicious cycle of hypoglycemia.Cortisol has been proposed to play a role in blunting neuroendocrine and metabolic responses to subsequent hypoglycemia (8,9). Similar to antecedent hypoglycemia, antecedent elevations of cortisol through infusion of cortisol (9) or adrenocorticotropic hormone (ACTH) (10) blunted neuroendocrine and metabolic counterregulatory responses to subsequent day 2 hypoglycemia in nondiabetic...

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“…To date, studies have not provided a complete understanding of the relationship between a decrement in the plasma glucose level and glucagon or insulin secretion, because the insulin level itself has been elevated to decrease the glucose level, and insulin per se can affect not only its own secretion (1), but also the release of other counterregulatory hormones, including glucagon (2)(3)(4)(5)(6)(7)(8)(9)(10)(11). Hyperinsulinemia, when paired with euglycemia, is known to increase the plasma concentrations of cortisol (5,6) and norepinephrine (7,8), but to decrease the plasma glucagon level (3,5,9). This decrease is thought to occur via a direct inhibitory effect on the ␣-cell (10,11).…”

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confidence: 99%

α- and β-Cell Responses to Small Changes in Plasma Glucose in the Conscious Dog

et al. 2001

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The responses of the pancreatic ␣-and ␤-cells to small changes in glucose were examined in overnight-fasted conscious dogs. Each study consisted of an equilibration (-140 to -40 min), a control (-40 to 0 min), and a test period (0 to 180 min), during which BAY R3401 (10 mg/kg), a glycogen phosphorylase inhibitor, was administered orally, either alone to create mild hypoglycemia or with peripheral glucose infusion to maintain euglycemia or create mild hyperglycemia. Drug administration in the hypoglycemic group decreased net hepatic glucose output (NHGO) from 8.9 ± 1.7 (basal) to 6.0 ± 1.7 and 5.8 ± 1.0 µmol · kg -1 · min -1 by 30 and 90 min. As a result, the arterial plasma glucose level decreased from 5.8 ± 0.2 (basal) to 5.2 ± 0.3 and 4.4 ± 0.3 mmol/l by 30 and 90 min, respectively (P < 0.01). Arterial plasma insulin levels and the hepatic portalarterial difference in plasma insulin decreased (P < 0.01) from 78 ± 18 and 90 ± 24 to 24 ± 6 and 12 ± 12 pmol/l over the first 30 min of the test period and decreased to 18 ± 6 and 0 pmol/l by 90 min, respectively. The arterial glucagon levels and the hepatic portal-arterial difference in plasma glucagon increased from 43 ± 5 and 4 ± 2 to 51 ± 5 and 10 ± 5 ng/l by 30 min (P < 0.05) and to 79 ± 16 and 31 ± 15 ng/l by 90 min (P < 0.05), respectively. In euglycemic dogs, the arterial plasma glucose level remained at 5.9 ± 0.1 mmol/l, and the NHGO decreased from 10 ± 0.6 to -3.3 ± 0.6 µmol · kg -1 · min -1 (180 min). The insulin and glucagon levels and the hepatic portal-arterial differences remained constant. In hyperglycemic dogs, the arterial plasma glucose level increased from 5.9 ± 0.2 to 6.2 ± 0.2 mmol/l by 30 min, and the NHGO decreased from 10 ± 1.7 to 0 µmol · kg -1 · min -1 by 30 min. The arterial plasma insulin levels and the hepatic portal-arterial difference in plasma insulin increased from 60 ± 18 and 78 ± 24 to 126 ± 30 and 192 ± 42 pmol/l by 30 min, after which they averaged 138 ± 24 and 282 ± 30 pmol/l, respectively. The arterial plasma glucagon levels and the hepatic portal-arterial difference in plasma glucagon decreased slightly from 41 ± 7 and 4 ± 3 to 34 ± 7 and 3 ± 2 ng/l during the test period. These data show that the ␣-and ␤-cells of the pancreas respond as a coupled unit to very small decreases in the plasma glucose level. Diabetes 50:367-375, 2001 G lucagon secretion increases in response to a decrease in the plasma glucose concentration and decreases in response to a rise in the plasma glucose level. Furthermore, insulin has been postulated to exert a paracrine influence on glucagon secretion when its release is modified in response to changes in the plasma glucose concentration. To date, studies have not provided a complete understanding of the relationship between a decrement in the plasma glucose level and glucagon or insulin secretion, because the insulin level itself has been elevated to decrease the glucose level, and insulin per se can affect not only its own secretion (1), but also the release of other counterregulatory hormones, inclu...

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Hyperinsulinemia Suppresses Glucose Utilization in Specific Brain Regions:In VivoStudies Using the Euglycemic Clamp in the Rat

Cited by 67 publications

References 47 publications

Different Brain Responses to Hypoglycemia Induced by Equipotent Doses of the Long-Acting Insulin Analog Detemir and Human Regular Insulin in Humans

Different Brain Responses to Hypoglycemia Induced by Equipotent Doses of the Long-Acting Insulin Analog Detemir and Human Regular Insulin in Humans

Cortisol Acts Through Central Mechanisms to Blunt Counterregulatory Responses to Hypoglycemia in Conscious Rats

α- and β-Cell Responses to Small Changes in Plasma Glucose in the Conscious Dog

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