TRANSACTIONS OF THE AMERICAN CLINICAL AND CLIMATOLOGICAL ASSOCIATION, VOL. 125, 2014

MECHANISMS OF HYPOGLYCEMIA AND EXERCISEASSOCIATED AUTONOMIC DYSFUNCTION STEPHEN N. DAVIS, MBBS, FRCP, FACP, and (by invitation) DONNA TATE, MS, and MAKA S. HEDRINGTON, MD BALTIMORE, MD

ABSTRACT It is well established that diabetes can lead to multiple microvascular and macrovascular complications. Several large scale randomized multicenter studies have shown that intensifying glucose control decreases microvascular and, to a certain extent, macrovascular complications of diabetes. However, intensifying glucose control in both type 1 and type 2 diabetes increases the risk of developing hypoglycemia, one of the most feared complications of people with the disease. The mechanisms responsible for intensive therapy causing increased hypoglycemia in patients with diabetes have been extensively investigated. It is now known that a single episode of hypoglycemia can blunt the body’s normal counterregulatory defenses against subsequent hypoglycemia or exercise. Similarly, a single bout of exercise can also blunt counterregulatory responses against subsequent hypoglycemia. Both neuroendocrine and autonomic nervous system responses are reduced by prior hypoglycemia and/or exercise. Work from several laboratories has identified multiple physiologic mechanisms involved in the pathogenesis of this hypoglycemia and exercise-associated counterregulatory failure. By continuing to study these mechanisms, some promising approaches to amplify counterregulatory responses to hypoglycemia are being discovered.

INTRODUCTION Large, multicenter randomized controlled trials in patients with type 1 (T1DM) or type 2 diabetes mellitus (T2DM) have shown that intensive metabolic control can reduce microvascular and to a certain extent macrovascular complications of the disease (1,2). However, all have shown that with better glucose control, as measured by decreasing glycosylated hemoglobin, the rates of severe hypoglycemia have Correspondence and reprint requests: Stephen N. Davis, MBBS, FRCP, FACP, 22 S. Greene Street, Room N3W42, Baltimore, MD 21201, Tel: 410-328-2488, Fax: 410-328-8688, E-mail: [email protected]. Potential Conflicts of Interest: None Disclosed.

281

282

STEPHEN N. DAVIS ET AL

increased. Thus, severe hypoglycemia threatens to limit the widespread implementation and therefore advantages of intensive therapy in diabetic subjects. The rate of severe hypoglycemia is also related to disease duration in both T1DM and T2DM (2). People with T2DM treated for less than 2 years with oral medications or insulin had a reduced incidence of hypoglycemic events as compared to those treated with insulin and oral medications for more than 5 years. However, in T1DM individuals with disease duration of more than 5 years, the rate of severe hypoglycemic episodes is increased a further twofold (2). With disease progression there is also a reduced homeostatic, counterregulatory response to decreasing blood glucose levels. When blood glucose levels decrease a well-coordinated response of physiologic counterregulatory mechanisms are activated. The first is to decrease endogenous insulin secretion which occurs at plasma glucose levels of ⬃80 mg/dL. As glucose levels continue to decrease (⬃70 mg/dL), the powerful, metabolic counterregulatory (anti-insulin) hormones glucagon, epinephrine, growth hormone, cortisol, norepinephrine, aldosterone, and adrenocorticotropic hormone are released. This in turn stimulates hepatic glucose production and adipose tissue lipolysis (release of glycerol and free fatty acids) and inhibits skeletal muscle glucose uptake, thereby increasing circulating glucose. In an individual with T1DM and those with longer duration T2DM, there is either none or very little endogenous insulin to turn off and thus the first line of defense against decreasing plasma glucose levels is lost. The patient is therefore exposed to the presence of exogenous insulin that cannot be modulated, and if an imbalance is created with reduced energy intake or increased exercise, then a risk of hypoglycemia is created. With disease progression, glucagon responses (an important second line of defense against decreasing plasma glucose levels) are either completely lost in T1DM or diminished in T2DM, which therefore places epinephrine as the critical defense against hypoglycemia (3). Unfortunately, with increasing disease duration, intensive glucose control, and hypoglycemic episodes, even epinephrine responses become attenuated (4). Furthermore, symptom awareness to hypoglycemia also becomes attenuated. This is relevant, as epinephrine can compensate for a reduced glucagon response during hypoglycemia. If glucagon and epinephrine counterregulatory mechanisms fail, then the risk for severe hypoglycemia is increased ⬃25-fold. Thus, with disease progression and repeated hypoglycemia, all of the body’s critical physiologic defenses against decreasing blood glucose levels become impaired, creating a vicious cycle for further hypoglycemia.

HYPOGLYCEMIA AND AUTONOMIC DYSFUNCTION

283

EXERCISE Exercise is a cornerstone to managing diabetes. In individuals taking insulin or insulin secretagogue medications, even moderate exercise can lead to hypoglycemia. Exercise can result in hypoglycemia during and any time up to 24 hours after the bout. The causes for exercise-associated hypoglycemia are multifactorial and traditionally have included exercise-associated increases in insulin sensitivity and thus glucose uptake, inadequately replenishing endogenous hepatic and muscle glycogen stores, and balancing oral carbohydrate intake with exogenous insulin delivery. More recently, several studies have shown that hypoglycemia can also blunt counterregulatory responses to subsequent exercise (5–7). Two 2-hour periods of antecedent hypoglycemia (50 mg/dL) blunted exercise-induced increases in glucagon, catecholamine, cortisol, endogenous glucose production (EGP), and lipolysis during next-day exercise (90 minutes at 50%VO2max) in both healthy individuals and people with T1DM (8, 9). These blunting effects can be elicited by even mild antecedent hypoglycemia (70 mg/dL) (10) (Fig. 1). We also wanted to study the converse and ask the question whether exercise can blunt counterregulatory responses to subsequent hypoglycemia. Healthy individuals were studied during 2-day experiments with participants on day 1 randomized to either euglycemic rest or euglycemic exercise. Day 2 was similar for both protocols and involved a single hypoglycemic clamp (50 mg/dL) lasting for 2 hours. During the final 30 minutes of day 2 hypoglycemia, epinephrine, glucagon, muscle sympathetic nerve activity (a direct measure of sympathetic output), and EGP responses were all significantly blunted after day 1 exercise compared with day 1 rest (P ⬍ .005) (11) . Similar blunting effects were observed acutely when individuals with T1DM underwent a single 90-minute bout of cycling exercise in the morning, followed by a 2-hour period of controlled hypoglycemia in the afternoon (7). These data show that a feed-forward vicious cycle can be acutely created (in a few hours) in both T1DM and healthy patients, whereby exercise and hypoglycemia reciprocally blunt counterregulatory responses to the other stimulus. Furthermore, exercise and hypoglycemia were found to have equivalent blunting effects on autonomic nervous system (ANS) and neuroendocrine responses during each stress. CARDIOVASCULAR EFFECTS OF HYPOGLYCEMIA Cardiovascular (CV) disease is a major cause of death in T2DM patients. Heart attack and stroke are increased by more than twofold

284

STEPHEN N. DAVIS ET AL

*

120

80

40

0

15

10

Δ Cortisol μg/dl

Δ Glucagon pg/ml

Δ Epinephrine pg/ml

Incremental Responses During Day 2 Exercise

*

5

0

15

* 10

5

0

Day 1 Eugly

Day 1 Hypo 70

Day 1 Hypo 60

Day 1 Hypo 50

FIG. 1. Plasma incremental epinephrine, glucagon and cortisol levels during day 2 exercise (90 minutes of cycling at ⬃50% VO2max) in 22 patients (11 males/11 females) with T1DM. Data are group means ⫾ SE. On the previous day, patients had undergone two 120-minute hyperinsulinemic clamps at either euglycemia (EUGLY) or hypoglycemia of 90, 70, 60, or 50 mg/dL (HYPO 70, HYPO 60, HYPO 50, respectively). *P ⬍ .05 compared to levels of hypoglycemia (hypo).

in persons with diabetes. Hypoglycemia, as a consequence of intensive as well as standard diabetes treatment, is associated with increased CV morbidity and mortality (12–15). Several large scale studies in T2DM have investigated whether intensive metabolic control results in CV improvements. The Veterans Administration Diabetes Trial (VADT), the Action to Control Cardiovascular Risk in Diabetes (ACCORD) (16), and the Action in Diabetes and Vascular disease; preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) study all showed a significantly higher rate of severe hypoglycemia in the intensive group than the standard group (12). However, severe hypoglycemia was not

HYPOGLYCEMIA AND AUTONOMIC DYSFUNCTION

285

confined to the intensively treated T2DM individuals in these studies. High rates of severe hypoglycemia were observed in “standard treatment” patients who had HBA1c values of ⬃9% and were trying to improve this modest level of glucose control. In all three studies there was a significant association between severe hypoglycemia and CV morbidity and death. In ACCORD and VADT there was an even stronger risk for CV mortality after severe hypoglycemia in the standard therapy group as compared to intensively treated patients. Additionally, a recent large population study has also shown that hypoglycemia is associated with increased risk of CV events in patients who have T2DM (17). Supplementing outpatient research work, the National Institute for Health and Care Excellence (NICE) sugar study also showed that intensive glucose control increased mortality among adults in inpatient intensive care unit settings (18). Hanefeld et al reviewed 88 studies in which hypoglycemia triggered pathophysiologic changes that could potentially increase the risk of CV adverse events (19). The authors grouped those changes into several categories, one of which was release of catecholamines. Normal physiologic effects of catecholamines include increases in heart rate, blood pressure, peripheral resistance, and blood glucose level. In diabetic individuals with pre-existing CV disease and endothelial dysfunction, the resulting elevated blood pressure, heart rate, and peripheral resistance could potentially increase mortality (20). Acute arrhythmias secondary to epinephrine and increased sympathetic nervous system activity during hypoglycemia have also been proposed to result in morbidity and possibly mortality due to pro-arrythmogenic prolongation of QTc interval (20 –24). Acute and repeated hypoglycemia can lead to myocardial ischemia, arrhythmias, and cerebral damage (24 –26). Hypoglycemia has been shown to increase a number of inflammatory, thrombotic, fibrinolytic, and oxidative stress biomarkers (27,28). Such changes, especially in the presence of a compromised vasculature, may further contribute to atherosclerotic processes. Gogitidze et al investigated vascular consequences of acute hypoglycemia in healthy subjects and T1DM (29). Platelet aggregation (P-selectin) and plasminogen activator inhibitor 1 (PAI-1) levels were significantly increased (P ⬍ .05) during hypoglycemic clamps compared with euglycemia indicating an increased prothrombotic state (Fig. 2). In addition, repeated hypoglycemia also resulted in increased pro-inflammatory and pro-atherothrombotic levels of biomarkers compared with euglycemia. These results indicate that both acute and repeated hypoglycemia can trigger pro-atherothrombotic mechanisms in both healthy and T1DM individuals.

286

STEPHEN N. DAVIS ET AL

Incremental Responses During Hypoglycemia Δ PAI-1 ng/ml

40

*

20

*

0 -20

Δ P selectin pg/ml

-40 40

*

*

20 0 -20 -40 Healthy Control Eugly

Healthy Control Hypo

T1DM Eugly

T1DM Hypo

FIG. 2. Effects of hyperinsulinemic euglycemia and hypoglycemia in overnight fasted healthy controls and T1DM on vascular biologic markers. Responses of PAI-1 and P-selectin are significantly increased (*P ⬍ .05) during hypoglycemia as compared to euglycemia in healthy controls and T1DM.

Wright et al observed similar results as well as significant increases in P-selectin at both 6 and 24 hours after the initiation of the hypoglycemic clamp in non-diabetics (28). Similar deleterious vascular biologic effects also occur during hypoglycemia in T2DM. REVERSING COUNTERREGULATORY DEFICIENCIES Hypoglycemia is the complication of diabetes most feared by insulinrequiring diabetics. Identifying strategies to avoid hypoglycemia and its consequences while maintaining good glucose control is an important goal in diabetes management. Several studies have focused on reversing defective counterregulatory responses and increasing hypoglycemic symptom awareness through strict avoidance of hypoglycemia. Scrupulous avoidance of hypoglycemia over a period of weeks or a few months has been shown to improve symptom awareness and to a certain extent also improve counterregulatory hormone responses. Liu et al determined that by increasing mean blood glucose levels to 150 –180 mg/dL over a 3-month period, symptom responses, epinephrine, and growth hormone levels were increased during a hypoglycemic

HYPOGLYCEMIA AND AUTONOMIC DYSFUNCTION

287

clamp compared to responses before the glycemic increase (30). Fritsche et al also showed that by decreasing the frequency of hypoglycemia that autonomic and neuroglycopenic symptom responses can be improved (31). The drawback to improving hypoglycemia awareness and counterregulatory responses by relaxing glucose control is the increased risk of microvascular and macrovascular diabetic complications. Therefore, there is a need to identify other targets to improve counterregulatory responses without causing deterioration in glycemic control. Selective serotonin reuptake inhibitors (SSRIs) have effects on hippocampal, hypothalamic, and frontal cortical regions of the brain. These areas are known to modulate the ANS and neuroendocrine responses to hypoglycemia. Because SSRIs block norepinephrine transport, augmented sympathetic nervous system activity would be a logical consequence of the treatment (32–34). This was shown by studies in rodents and our work in humans, which clearly revealed that counterregulatory responses to hypoglycemia were significantly enhanced after treatment with SSRIs (33–35). Briscoe et al investigated the effects of 6 weeks of treatment with the SSRI fluoxetine on the counterregulatory responses to hypoglycemia in healthy subjects (34) and individuals with T1DM (35) (Fig. 3). After fluoxetine treat1800

*

Basal Final 30 min

600

*

1200

900

600

Norepinephrine (pg/ml)

Epinephrine (pg/mL)

1500 450

300

150

300

0

PRE-SSRI POST-SSRI POST PLACEBO

0

PRE-SSRI POST-SSRI POST PLACEBO

FIG. 3. Plasma epinephrine and norepinephrine levels (mean ⫾ SE) during hyperinsulinemic hypoglycemic clamp studies before and after 6 weeks of fluoxetine (SSRI) or placebo. Plasma epinephrine and norepinephrine levels are significantly increased (*P ⬍ .01) after fluoxetine as compared to pretreatment and placebo values.

288

STEPHEN N. DAVIS ET AL

ment, catecholamine, muscle sympathetic nervous system activity, EGP, and lipolytic responses were significantly higher during hypoglycemia compared to baseline and the placebo group. Animal data has also shown significant improvements in counterregulatory hormone responses, especially epinephrine, with SSRI treatment (33). This suggests that serotonin and its transmission system play a significant role in regulating the sympathetic nervous system during hypoglycemia. Other targets may include opioid receptor blockade as shown by Vele et al. Blockade of endogenous opioids with naloxone during antecedent hypoglycemia improved counterregulatory responses in patients with T1DM by enhancing epinephrine responses and restoring EGP (36). Stimulation of hypothalamic adenosine monophosphate-activated protein kinase (AMPK) may also be required for normal glucose sensing. Blunted counterregulatory responses (glucagon and epinephrine) in rats can be rescued by stimulation of AMPK via direct injection of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) into the ventral medial hypothalamic nucleus in both non-diabetic and diabetic rats (37–39). Our lab also has shown that the inhibitory neurotransmitter GABAA can markedly blunt the counterregulatory responses to hypoglycemia in humans (40). Supporting these findings, animal data has shown that GABAA receptor antagonism in the ventromedial hypothalamus of rats enhances the counterregulatory response to hypoglycemia and rescues the blunting effects of repeated hypoglycemia (41,42). Ongoing elucidation of the above mechanisms may reveal some promising approaches to amplify the counterregulatory responses to hypoglycemia. CONCLUSION Multiple mechanisms are involved in the pathogenesis of hypoglycemia and exercise-associated autonomic failure. Offsetting the beneficial effects of exercise in diabetes management, exercise regimes often unfortunately result in hypoglycemia in persons with diabetes. Antecedent moderate exercise can blunt counterregulatory responses during subsequent hypoglycemia. Similarly, antecedent hypoglycemia can also blunt subsequent hypoglycemia and exercise. This vicious cycle of repeated hypoglycemia can cause a significant obstacle to improving glucose management in the person who has diabetes. Besides classic counterregulatory responses, such as sympathoadrenal stimulation, glucagon release, and inhibition of insulin, hypoglycemia also triggers changes in fibrinolytic balance, platelet activation, and decreases in endothelial function. These changes can potentially

HYPOGLYCEMIA AND AUTONOMIC DYSFUNCTION

289

increase CV morbidity and mortality. Severe hypoglycemia is associated with increased mortality in patients with long-standing T2DM. Novel approaches to amplify counterregulatory responses during hypoglycemia are under investigation and show early promise to reduce the incidence of severe hypoglycemia while potentially maintaining glucose control and thus improving quality of life. REFERENCES 1. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329(14):977– 86. 2. UK Hypoglycaemia Study Group. Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia 2007;50(6):1140 –7. 3. Gerich J, Noacco C, Karam J, Forsham P. Lack of glucagon response to hypoglycemia in diabetes: evidence for an intrinsic pancreatic alpha-cell defect. Science 1973; 182:171. 4. Cryer PE. Hypoglycemia: the limiting factor in the management of IDDM. Diabetes 1994;43:1378 – 89. 5. Davis SN, Tate D. Effects of morning hypoglycemia on neuroendocrine and metabolic responses to subsequent afternoon hypoglycemia. J Clin Endocrinol Metabol 2001;86(5):2043–50. 6. Davis SN, Shavers C, Mosqueda-Garcia R, Costa F. Effects of differing antecedent hypoglycemia on subsequent counterregulation in normal humans. Diabetes 1997;46:1328 –35. 7. Sandoval DA, Guy DL, Richardson MA, Ertl AC, Davis SN. Acute, same-day effects of antecedent exercise on counterregulatory responses to subsequent hypoglycemia in type 1 diabetes mellitus. Am J Physiol Endocrinol Metab 2006;290:E1331– 8. 8. Davis SN, Galassetti P, Wasserman DH, Tate D. Effects of antecedent hypoglycemia on subsequent counterregulatory responses to exercise. Diabetes 2000;49:73– 81. 9. Galassetti P, Tate D, Neill RA, Morrey S, Wasserman DH, Davis SN. Effect of antecedent hypoglycemia on counterregulatory responses to subsequent euglycemic exercise in type 1 diabetes. Diabetes 2003;52:1761–9. 10. Galassetti P, Tate D, Neill RA, Richardson A, Leu SY, Davis SN. Effect of differing antecedent hypoglycemia on counterregulatory responses to exercise in type 1 diabetes. Am J Physiol Endocrinol Metab 2006;290:E1109 –17. 11. Galassetti P, Mann S, Tate D, et al. Effects of antecedent prolonged exercise on subsequent counterregulatory responses to hypoglycemia. Am J Physiol Endocrinol Metab 2001;280:E908 –17. 12. The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560 –72. 13. Wei M, Gibbons LW, Mitchell TL, Kampert JB, Stern MP, Blair SN. Low fasting plasma glucose level as a predictor of cardiovascular disease and all-cause mortality. Circulation 2000;101(17):2047–52. 14. Johnston SS, Conner C, Aagren M, Smith DM, Bouchard J, Brett J. Evidence linking hypoglycemic events to an increased risk of acute cardiovascular events in patients with type 2 diabetes. Diabetes Care 2011;34(5):1164 –70.

290

STEPHEN N. DAVIS ET AL

15. Zoungas S, Patel A, Chalmers J, et al. Severe hypoglycemia and risks of vascular events and death. N Engl J Med 2010;363(15):1410 – 8. 16. The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;258:2545–59. 17. Hsu P, Sung S, Cheng H, et al. Association of clinical symptomatic hypoglycemia with cardiovascular events and total mortality in type 2 diabetes: a nationwide population-based study. Diabetes Care 2013;36(4):894 –900. 18. NICE-SUGAR Study Investigators. Hypoglycemia and risk of death in critically ill patients. N Engl J Med 2012;367(12):1108 –18. 19. Hanefeld M1, Duetting E, Bramlage P. Cardiac implications of hypoglycaemia in patients with diabetes — a systematic review. Cardiovasc Diabetol 2013;12:135. 20. Wright RJ, Frier BM. Vascular disease and diabetes: is hypoglycaemia an aggravating factor? Diabetes Metab Res Rev 2008;24(5):353– 63. 21. Chelliah YR. Ventricular arrhythmias associated with hypoglycaemia. Anaesth Intensive Care 2000;28(6):698 –700. 22. Collier A, Matthews DM, Young RJ, Clarke BF. Transient atrial fibrillation precipitated by hypoglycaemia: two case reports. Postgrad Med J 1987;63(744):895–7. 23. Lindstrom T, Jorfeldt L, Tegler L, Arnqvist HJ. Hypoglycaemia and cardiac arrhythmias in patients with type 2 diabetes mellitus. Diabet Med 1992;9(6):536 – 41. 24. Robinson RT, Harris ND, Ireland RH, Lee S, Newman C, Heller SR. Mechanisms of abnormal cardiac repolarization during insulin-induced hypoglycemia. Diabetes 2003;52(6):1469 –74. 25. Dave KR, Tamariz J, Desai KM, et al. Recurrent hypoglycemia exacerbates cerebral ischemic damage in streptozotocin-induced diabetic rats. Stroke 2011;42(5):1404 –11. 26. Gimenez M, Gilabert R, Monteagudo J, et al. Repeated episodes of hypoglycemia as a potential aggravating factor for preclinical atherosclerosis in subjects with type 1 diabetes. Diabetes Care 2011;34(1):198 –203. 27. Dandona P, Chaudhuri A, Dhindsa S. Proinflammatory and prothrombotic effects of hypoglycemia. Diabetes Care 2010;33(7):1686 –7. 28. Wright RJ, Newby DE, Stirling D, Ludlam CA, Macdonald IA, Frier BM. Effects of acute insulin-induced hypoglycemia on indices of inflammation: putative mechanism for aggravating vascular disease in diabetes. Diabetes Care 2010;33(7):1591–7. 29. Gogitidze N, Hedrington M, Briscoe V, Tate, D, Davis SN. The effects of hypoglycemia on atherothrombotic balance in type 1 DM and healthy man. Diabetes Care 2010;33(7):1529 –35. 30. Liu D, McManus RM, Ryan EA. Improved counter-regulatory hormonal and symptomatic responses to hypoglycemia in patients with insulin-dependent diabetes mellitus after 3 months of less strict glycemic control. Clin Invest Med 1996;19:71– 82. 31. Fritsche A, Stefan N, Haring H, Gerich J, Stumvoll M. Avoidance of hypoglycemia restores hypoglycemia awareness by increasing beta-adrenergic sensitivity in type 1 diabetes. Ann Intern Med 2001;134:729 –36. 32. Blardi P, de Lalla A, Auteri A, Iapichino S, Dell’Erba A, Castrogiovanni P. Plasma catecholamine levels after fluox treatment in depressive patients. Neuropsychobiology 2005;51:72– 6. 33. Sanders NM, Wilkinson CW, Taborsky GJ, et al. The selective serotonin reuptake inhibitor sertraline enhances counterregulatory responses to hypoglycemia. Am J Physiol Endocrinol Metab 2008;294:E853– 60. 34. Briscoe VJ, Ertl AC, Tate DB, Dawling S, Davis SN. Effects of a selective serotonin reuptake inhibitor, fluoxetine, on counterregulatory responses to hypoglycemia in healthy man. Diabetes 2008;57:2453– 60.

HYPOGLYCEMIA AND AUTONOMIC DYSFUNCTION

291

35. Briscoe VJ, Ertl AC, Tate DB, Davis SN. Effects of the selective serotonin reuptake inhibitor fluoxetine on counterregulatory responses to hypoglycemia in individuals with type 1 diabetes. Diabetes 2008;57(12):3315–22. 36. Vele S, Milman S, Shamoon H, Gabriely I. Opioid receptor blockade improves hypoglycemia-associated autonomic failure in type 1 diabetes mellitus. J Clin Endocrinol Metab 2011;96(11):3424 –31. 37. Alquier T, Kawashima J, Tsuji Y, Kahn BB. Role of hypothalamic adenosine 5⬘monophosphate-activated protein kinase in the impaired counterregulatory response induced by repetitive neuroglucopenia. Endocrinology 2007;148(3):1367–75. 38. McCrimmon RJ, Fan X, Cheng H, et al. Activation of AMPactivated protein kinase within the ventromedial hypothalamus amplifies counterregulatory hormone responses in rats with defective counterregulation. Diabetes 2006;55:1755– 60. 39. Fan X, Ding Y, Brown S, et al. Hypothalamic AMP-activated protein kinase activation with AICAR amplifies counterregulatory responses to hypoglycemia in a rodent model of type 1 diabetes. Am J Physiol Regul Integr Comp Physiol 2009;296:R1702– 8. 40. Hedrington MS, Farmerie S, Ertl AC, Wang Z, Tate DB, Davis SN. Effects of antecedent GABAA activation with alprazolam on counterregulatory responses to hypoglycemia in healthy humans. Diabetes 2010;59:1074 – 81. 41. Chan O, Cheng H, Herzog R, et al. Increased GABAergic tone in the ventromedial hypothalamus contributes to suppression of counterregulatory responses after antecedent hypoglycemia. Diabetes 2008;57:1363–70. 42. Chan O, Zhu W, Ding Y, McCrimmon RJ, Sherwin RS. Blockade of GABA(A) receptors in the ventromedial hypothalamus further stimulates glucagon and sympathoadrenal but not the hypothalamo-pituitary-adrenal response to hypoglycemia. Diabetes 2006;55:1080 –7.

DISCUSSION Thorner, Charlottesville: That was a very beautiful presentation. I guess my question really is, is the issue really that one wants to avoid this or is it that we need to avoid the treatments that are given for type 2 diabetics? Because it’s been clearly shown in the UKPDS study that metformin is the only drug that actually improves the outlook and sulfonylureas and insulin do not. So it seems to me that the approach is wrong, and the concept that insulin resistance is something that needs to be overcome is also wrong. It’s probably a protective mechanism. Davis, Baltimore: So Michael, your points are very well taken. The issue is that in type 1 and long-standing type 2 diabetes, when you have critical insulin deficiency you’ve got to replace the hormone. If you’re going to give insulin — because even the glucagonlike peptide-1 agonists don’t have enough oomph if the beta cells are gone — I don’t know how you would maintain glycemia. Thorner, Charlottesville: I think that there are some type 2 diabetics that really are profoundly insulin-deficient; the majority are not. I’ve been actually studying some of these patients — not that I am a diabetologist — and basically by fasting them and actually getting them to eat a vegan diet and putting them on metformin, you can take them off hundreds of units of insulin. You have to allow their glucoses to rise, but within a few weeks, their glucoses come down. They don’t come down to normal immediately. But I’ve had patients who have had blood sugars in the 500s who now, years later, have a hemoglobin A1cs of about 5.2, and they are only on metformin having been on hundreds of units of insulin for years.

292

STEPHEN N. DAVIS ET AL

Davis, Baltimore: So congratulations to you if you can get your diabetic patients on a vegan diet and lose weight. Do you want to come to Baltimore? Gershon, New York: I was wondering what you thought exactly of the mechanism of the action of the SSRIs. Among other things, the SSRIs — although they are called selective or not selective — and particularly fluoxetine, have both the ability to interfere with the uptake of catecholamines, particularly in a high dose — as serotonin — and have an amphetamine-like effect. So the question is, how much of the effect of fluoxetine is due to blunting or potentiating the catecholamine effect that you see, and how much is a central effect? Would it be possible that a drug like methylphenidate or dextroamphetamine sulfate would be even more effective than Prozac? Davis, Baltimore: Thank you. I think that is an outstanding question, and fortunately the NHLBI and NIDDK agree with that, because we are funded to do just that study — give Ritalin to have a look, and look at the mechanism of norepinephrine transport on this. Yes they do; acutely they do improve that. There are rat studies to show that there are cells around the brainstem and fourth ventricle that are affected, per se, by serotonin re-uptake, which tends to stimulate catecholamine transmission (autonomic transmission). So I think it is a central effect rather than a peripheral effect.

Mechanisms of hypoglycemia and exercise-associated autonomic dysfunction.

It is well established that diabetes can lead to multiple microvascular and macrovascular complications. Several large scale randomized multicenter st...
111KB Sizes 3 Downloads 3 Views