Counterregulatory Hormonal Responses to Rapid Glucose Lowering in Diabetic Man

Lilavivathana, Usah; Brodows, Robert G.; Woolf, Paul D.; Campbell, Robert G.

doi:10.2337/diab.28.10.873

Cited by 47 publications

(24 citation statements)

References 12 publications

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“…Posture affects responses to hypoglycaemia [11,12]. In theory, it is possible that the rate of decreasing blood glucose in the postprandial condition and in the sitting position, exerts effects on responses to hypoglycaemia which differ from those obtained in patients fasting and lying in bed [4,5,6,7,8].…”

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“…A number of studies in healthy, non-diabetic subjects and in patients with Type I diabetes [4,5,6,7], dealt with these phenomena in the post-absorptive state and concluded that the rate of decreasing blood glucose affects neither counterregulatory hormone secretion, nor generation of symptoms in response to insulin-induced hypoglycaemia, nor cognitive function. Therefore, so far the nadir of blood glucose concentration achieved is regarded the main factor controlling the magnitude of responses to hypoglycaemia.…”

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confidence: 99%

“…All previous studies examining the rate of decreasing blood glucose concentrations on responses to hypoglycaemia [4,5,6,7,8] have been carried out in the post-absorptive condition and in the lying position. However, in the daily life of patients with Type I diabetes, hypoglycaemia could occur in the postprandial condition, particularly when the insulin dose is inappropriately high for the carbohydrate content of the meal.…”

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Rate of fall of blood glucose and physiological responses of counterregulatory hormones, clinical symptoms and cognitive function to hypoglycaemia in Type I diabetes mellitus in the postprandial state

et al. 2003

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Aims/hypothesis. The aim of this study was to establish the effect of a rate of decreasing plasma glucose concentrations on responses to hypoglycaemia, i.e. release of counterregulatory hormones, perception of symptoms, deterioration of cognitive function, and rates of forearm noradrenaline spillover, in the postprandial condition and in the sitting position. Methods. We studied 11 subjects with Type I (insulindependent) diabetes mellitus, twice during clamped insulin-induced hypoglycaemia (2.4 mmol/l) after eating in the sitting position. On one occasion, plasma glucose was decreased at the rate of 0.1±0.003 mmol· min -1 ·l -1 (fast fall), on the other at the rate of 0.03±0.001 mmol·min -1 ·l -1 (slow fall). Subjects underwent a control euglycaemic clamp study as well. Results. In response to fast-fall as compared to slowfall hypoglycaemia, which was about 30 min longer, cognitive tasks were performed as follows: TrailMaking B, PASAT 2 s, Digit Vigilance Test and Verbal Memory deteriorated more, adrenaline increased less (2.8±0.5 vs 3.5±0.7 nmol/l, p=0.03), forearm noradrenaline spillover was greater (6.5±1.0 vs 5.2±0.4 pmol·min -1 ·100 ml -1 , p=0.04), and symptoms were no different. After recovery from hypoglycaemia, cognitive function was still deteriorated compared to the baseline with no difference between fast and slow-fall hypoglycaemia. The evident response of glucagon to postprandial hypoglycaemia contrasted with the blunted or absent response in the fasting state. Conclusion/interpretation. In the postprandial condition and sitting position, fast-fall hypoglycaemia is more dangerous than slow-fall, because it deteriorates cognitive function more, and activates responses of counterregulatory hormones less than slow-fall hypoglycaemia. [Diabetologia (2003) 46:53-64] Keywords Type I diabetes mellitus, postprandial hypoglycaemia, glucose counterregulation, cognitive dysfunction, forearm noradrenaline spillover. acting insulin analogue as compared to human regular insulin, the technique of s.c. injection, insulin sensitivity and meal size and composition, are usually considered the most important determinants of the rate of decreasing postprandial blood glucose concentrations. After s.c. injection of rapid-acting insulin analogues [1], the rate of decreasing blood glucose is greater than after injecting human regular insulin [2,3]. Therefore, it is expected that when hypoglycaemia is induced by mealtime administration of rapid-acting insulin analogue, the rate of decreasing blood glucose is greater than after injecting human regular insulin. In theory, different rates of decreasing blood glucose in the postprandial condition might result in different reWhen patients with Type I (insulin-dependent) diabetes mellitus experience hypoglycaemia after a subcutaneous (s.c.) injection of rapid-acting insulin at mealtime, blood glucose decreases to below normal concentrations at rates which can differ on different occasions. Among several factors, the injection of a rapid-

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confidence: 99%

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Rate of fall of blood glucose and physiological responses of counterregulatory hormones, clinical symptoms and cognitive function to hypoglycaemia in Type I diabetes mellitus in the postprandial state

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“…However, the fall in hepatic uptake of glycerol was unaffected by changes in glucagon and thus gluconeogenesis from this substrate was inhibited by insulin per se probably as a result of reduced lipolysis. The latter effect of insulin may explain the incomplete restoration of hepatic glucose production when hyperglucagonaemia was re-established during insulin infusion.Key words: Diabetes, insulin, glucagon, glycogenolysis, gluconeogenesis, dog.Fasting hyperglycaemia is associated with insulin-deficient diabetes and is accompanied by inappropriately raised plasma glucagon concentrations [1][2][3][4]. However, insulin treatment can reduce or even nonnalise glucagon levels in the diabetic dog [4,5] and man [6,7].…”

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“…Fasting hyperglycaemia is associated with insulin-deficient diabetes and is accompanied by inappropriately raised plasma glucagon concentrations [1][2][3][4]. However, insulin treatment can reduce or even nonnalise glucagon levels in the diabetic dog [4,5] and man [6,7].…”

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Role of glucagon suppression on gluconeogenesis during insulin treatment of the conscious diabetic dog

1987

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Summary. In seven insulin-deficient (< 3 mU/1) pancreatectomised dogs, the direct and glucagon-related indirect effects of intraportal insulin infusion (350 ~U/kg-min; 12 + 1 mU/1) on glucose production were determined. Insulin was infused for 300 min during which time the plasma glucagon concentration was allowed to fall (314+94 to 180+63 ng/l) for 150 min before being replaced by an infusion intraportally at 2.6ng/kg-rnin (323+61ng/1) for the remaining 150min. Glucose production and gluconeogenesis were determined using arterio-venous difference and tracer techniques. Insulin infusion shut off net hepatic glucose output and caused the plasma glucose, blood glycerol and plasma non-esterified fatty acid levels to fall. It caused the hepatic fractional extraction of alanine (0.41 +0.10 to 0.21 +0.06) and lactate (0.32__+0.09 to 0.04___0.03) to fall which increased their concentrations. When glucagon was replaced, all of these changes were fully or partly reversed with the exception of the changes in glycerol and nonesterified fatty acids. Indeed, 70% of the fall in hepatic glucose production and virtually 100% of the changes in lactate and alanine metabolism produced by basal insulin infusion were mediated by a fall in glucagon. However, the fall in hepatic uptake of glycerol was unaffected by changes in glucagon and thus gluconeogenesis from this substrate was inhibited by insulin per se probably as a result of reduced lipolysis. The latter effect of insulin may explain the incomplete restoration of hepatic glucose production when hyperglucagonaemia was re-established during insulin infusion.Key words: Diabetes, insulin, glucagon, glycogenolysis, gluconeogenesis, dog.Fasting hyperglycaemia is associated with insulin-deficient diabetes and is accompanied by inappropriately raised plasma glucagon concentrations [1][2][3][4]. However, insulin treatment can reduce or even nonnalise glucagon levels in the diabetic dog [4,5] and man [6,7]. Since both elevations in plasma insulin [8] and reductions in plasma glucagon [9] can reduce hepatic glucose production and gluconeogenesis, the aim of the present study was to determine the relative roles of the changes in insulin and glucagon which result from insulin infusion in reducing the hyperglycaemia and elevated gluconeogenesis apparent in overnight-fasted diabetic (pancreatectomised) dogs. This was accomplished by administering insulin alone via the portal circulation at a low infusion rate then re-establishing the starting glucagon levels in the second half of the study by intraportal infusion of glucagon coincident with the insulin infusion. Since the dogs were prepared with indwelling catheters in the left common hepatic vein, the portal vein and in the femoral artery, net hepatic balances of glucose and gluconeogenic substrates could be calculated using the arteriovenous difference technique. Materials and methods Animals and surgical proceduresEleven mongrel dogs (15-23 kg) of either sex were fed a normal diet (Kal Kan meat and Wayne Dog Chow, Wayne Meat Ration, Alli...

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Glucose transport in brain and retina: implications in the management and complications of diabetes

Kumagai

1999

Diabetes Metab. Res. Rev.

138

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Neural tissue is entirely dependent on glucose for normal metabolic activity. Since glucose stores in the brain and retina are negligible compared to glucose demand, metabolism in these tissues is dependent upon adequate glucose delivery from the systemic circulation. In the brain, the critical interface for glucose transport is at the brain capillary endothelial cells which comprise the blood±brain barrier (BBB). In the retina, transport occurs across the retinal capillary endothelial cells of the inner blood±retinal barrier (BRB) and the retinal pigment epithelium of the outer BRB. Because glucose transport across these barriers is mediated exclusively by the sodiumindependent glucose transporter GLUT1, changes in endothelial glucose transport and GLUT1 abundance in the barriers of the brain and retina may have profound consequences on glucose delivery to these tissues and major implications in the development of two major diabetic complications, namely insulin-induced hypoglycemia and diabetic retinopathy. This review discusses the regulation of brain and retinal glucose transport and glucose transporter expression and considers the role of changes in glucose transporter expression in the development of two of the most devastating complications of longstanding diabetes mellitus and its management.

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Counterregulatory Hormonal Responses to Rapid Glucose Lowering in Diabetic Man

Cited by 47 publications

References 12 publications

Rate of fall of blood glucose and physiological responses of counterregulatory hormones, clinical symptoms and cognitive function to hypoglycaemia in Type I diabetes mellitus in the postprandial state

Rate of fall of blood glucose and physiological responses of counterregulatory hormones, clinical symptoms and cognitive function to hypoglycaemia in Type I diabetes mellitus in the postprandial state

Role of glucagon suppression on gluconeogenesis during insulin treatment of the conscious diabetic dog

Glucose transport in brain and retina: implications in the management and complications of diabetes

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