Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT03538015 |
| Other study ID # |
IRB #108879 |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
April 22, 2019 |
| Est. completion date |
August 10, 2020 |
Study information
| Verified date |
November 2020 |
| Source |
University of Utah |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Type 1 diabetes mellitus (T1DM) can lead to cardiovascular, renal and neurological
complications if left poorly-controlled over prolonged periods of time. However, lowering
glycemic goals for diabetic patients increases their risk for hypoglycemia exposure.
Hypoglycemia is associated with symptoms such as heart palpitations, fatigue, shakiness,
anxiety, confusion, and blurred vision. Recurrent hypoglycemia leads to impairment of the
body's autonomic and symptomatic responses to this condition, and can result in loss of
awareness in the patient of the hypoglycemic state. Repeated incidences of hypoglycemia from
loss of this awareness can result in even more hypoglycemic episodes and more severe
outcomes, such as loss of consciousness, accidents, hospitalization and even death if left
untreated.
The aim of this study is to investigate whether adrenergic blockade through the use of
low-dose carvedilol treatment can improve hypoglycemia awareness and the counterregulatory
hormone responses to hypoglycemia in T1DM patients with impaired awareness of hypoglycemia.
Description:
Hypoglycemia elicits a multifaceted hormonal response that helps restore glycemic levels to
normal. As blood glucose levels start to fall, insulin secretion ceases. At the top of this
hierarchy of counterregulatory responses are glucagon and epinephrine which are the two
principal hormones that act rapidly to increase glucose production and inhibit glucose
utilization to raise plasma glucose levels back to normal. In cases of prolonged and/or more
severe hypoglycemia, growth hormone and cortisol are mobilized to stimulate the synthesis of
gluconeogenic enzymes and inhibit glucose utilization. In non-diabetic individuals, glucagon
and epinephrine are usually very effective and the latter responses are rarely required in
the acute situation. In contrast, impaired glucose counterregulation presents itself in
longstanding diabetes and with antecedent hypoglycemia. Within the first five years after the
onset of T1DM, the primary defense against hypoglycemia, the release of glucagon, either
becomes significantly attenuated or is completely absent in diabetic patients and this
impairment appears to be specific for the stimulus of hypoglycemia. Hence, patients with
diabetes primarily depend on the release of epinephrine as their main defense against
hypoglycemia. Unfortunately, with longer duration of diabetes and especially with poor
glycemic control, epinephrine secretion is also compromised, making these patients even more
vulnerable to the threat of hypoglycemia. In patients with diabetes, hypoglycemia arises from
the interplay of a relative excess of exogenous insulin and defective glucose
counterregulation and it remains a limiting factor in attaining proper glycemic management.
Both the Diabetes Control and Complications Trial (DCCT) conducted in Type 1 patients and the
United Kingdom Prospective Diabetes Study (UKPDS) conducted in Type 2 patients, have
established the importance of maintaining good glucose control over a lifetime of diabetes to
avoid cardiovascular, renal and neurological complications. However, lowering glycemic goals
for diabetic patients increases their risk for hypoglycemia exposure. According to the DCCT,
T1DM patients put on intensive insulin therapy, though having improved outcomes for diabetic
complications, are at a 3-fold higher risk of experiencing severe hypoglycemia compared to
those on conventional insulin therapy. Moreover, recent antecedent hypoglycemia reduces
autonomic (epinephrine) and symptomatic (which normally prompts behavioral defenses such as
eating) responses to subsequent bouts of hypoglycemia. Thus begins the vicious cycle of
recurrent hypoglycemia (RH) where hypoglycemia leads to further impairment of
counterregulatory responses which tin turn, begets more hypoglycemia and so forth. Because of
the imperfections of current insulin therapies, those patients attempting to achieve glycemic
control suffer an untold number of asymptomatic hypoglycemic episodes. Current estimates of
symptomatic hypoglycemic episodes range form 2-3 incidences per week on average and severe,
debilitating episodes occur one or twice each year. Therefore, developing therapies to
prevent or eliminate hypoglycemia is of great importance.
Sensors that detect changes in blood glucose levels and initiate glucose counterregulatory
responses have been identified in both the periphery and within the brain. These sensors have
been localized to the hepatic portal vein, the carotid body and the brain. In the brain, the
dominant sensors are located in the hypothalamus. While peripheral glucose sensors may play a
role in mediating the immediate counterregulatory responses to hypoglycemia, it is thought
that glucosensors located within the brain may have a redundant regulatory and/or modulatory
role in regulating glucose counterregulatory responses. It is well established that brain
glucose sensors are crucial for detecting falling blood glucose levels and for initiating
counterregulatory responses. These sensors are located in the hindbrain, the lateral
hypothalamus, the paraventricular nucleus, the dorsal hypothalamus and the ventromedial
hypothalamus (VMH). The neurons within the VMH contain much of the same glucose sensing
machinery as the pancreatic β-cells. To date, two main types of glucose sensing neurons have
been identified in the brain - those that increase their firing rate in response to increases
in glucose levels, the "glucose-excited" (GE) neurons and those that decrease their firing
rate in response to increases in glucose levels, the "glucose-inhibited" (GI) neurons. The
mechanism by which GE neurons sense changes in blood glucose concentrations is believed to be
similar to that used by pancreatic β-cells whereas GI neurons respond to decreases in ambient
glucose levels through activation of the metabolic fuel sensor, AMP kinase (AMPK), and
closure of chloride channels that result in increased activity of GI neurons. Although many
of these sensing components have been identified, it is still not entirely clear how glucose
sensing neurons regulate counterregulatory hormone release. It has been proposed that
alterations in the firing rates of VMH glucose sensing neurons in response to glucose or fuel
deficits can inhibit (as is the case for GE neurons) or stimulate (as is the case for GI
neurons) the exocytosis of vesicles containing neurotransmitters that can modulate the
counterregulatory hormone response.
The inhibitory neurotransmitter, GABA, and the stimulatory neurotransmitters, glutamate and
norepinephrine (NE), act within the VMH to suppress or stimulate the counterregulatory
responses to hypoglycemia, respectively. In response to an initial bout of hypoglycemia, VMH
GABA levels decrease while glutamate and NE levels increase, allowing for activation of the
counterregulatory hormone responses. While these studies underscore the importance of VMH
neurotransmitter signaling in regulating glucose homeostatic mechanisms, to date, the
mechanisms that lead to their dysregulation in models of counterregulatory failure are not
entirely clear. Recent evidence suggests that lactate, which serves as an alternate fuel
substrate in the brain, plays an important role in precipitating the defects noted above.
Lactate produced from neighboring astrocytes can supplement higher energy requirements during
periods of increased neuronal activity or when glucose supply is limited. If this is the
case, then lactate can be used in place of glucose as a fuel for VMH glucose sensing neurons,
preventing them from detecting a fall in glucose levels, causing (inhibitory) GABA tone to be
enhanced and (stimulatory) glutamate output to be reduced. Together, these actions ultimately
suppress the release of counterregulatory hormones. In recent years, it has been shown that
lactate levels are sensed by the brain and more specifically, can act in the hypothalamus to
regulate glucose homeostasis, appetite and body weight. Lactate prevents the activation of
hypothalamic neurons during glucose deprivation and more pertinent to this application,
attenuates glucose counterregulatory responses to hypoglycemia when locally administered into
the VMH. Data from the investigator's research group revealed VMH extracellular lactate
concentrations are elevated in RH and diabetic animals and in particular, these conditions
also increase expression of the lactate transporter in the VMH. When VMH lactate uptake is
pharmacologically inhibited, neurotransmitter and counterregulatory responses improve in both
RH and diabetic animals, suggesting lactate plays an important role in dysregulating
neurotransmitter systems in the VMH, which in turn, impairs counterregulatory responses.
Preliminary data suggests that therapeutic strategies that can reduce brain lactate levels,
may help restore hypothalamic glucose sensing mechanisms and the counterregulatory response
to hypoglycemia. Hence, identifying the mechanisms that increase VMH lactate levels may lead
to suitable therapeutic strategies to prevent hypoglycemia.
Norepinephrine can enhance lactate production from astrocytes and it can also increase the
uptake of lactate into neurons through the activation of β2-adrenergic receptors (β2AR),
potentially helping to coordinate both the supply and uptake of lactate into neurons.
Normally, in response to an acute bout of hypoglycemia, VMH NE levels rise and act through
β2ARs to enhance the sympathoadrenal response. Although activation of VMH β2ARs augments the
counterregulatory response during acute bouts of hypoglycemia, less is known about the
effects of RH on this neurotransmitter system. It has been reported that VMH NE levels are
not altered by successive bouts of hypoglycemia, suggesting activation of the VMH NE system
is not dampened by RH and that its suppressive effects on counterregulatory hormone release
may lie downstream of NE release. In support of this finding, adrenergic blockade during
antecedent bouts of hypoglycemia was shown to prevent counterregulatory failure in healthy
human subjects. Therefore, while acute activation of VMH adrenergic receptors may be
beneficial in its capacity to enhance the counterregulatory response, repeated activation of
this neurotransmitter system may contribute to counterregulatory failure, but the mechanisms
by which this occurs have not been fully identified.
To evaluate whether repeated activation of the VMH NE system contributes to counterregulatory
failure, NE was microinjected into the VMH of non-diabetic, hypoglycemia-naive rats for 3
hours/day for 3 consecutive days before subjecting the animals to a hypoglycemic glucose
clamp on day 4. Repeated activation of the VMH NE system in the absence of hypoglycemia,
increased VMH lactate levels and more importantly, blunted the counterregulatory hormone
responses to hypoglycemia. This phenomenon was recapitulated with microinjection of
salbutamol, a short-acting β2AR agonist, into the VMH using the same protocol as for NE,
suggesting the suppressive effects of NE are mediated through VMH β2ARs. In a subgroup of
animals treated with NE, uptake of lactate into neurons was blocked immediately prior to the
hypoglycemic clamp. In this group, the suppressive effects of NE treatment on glucose
counterregulation were completely abolished. Hence, preliminary data suggests that repeated
activation of the VMH NE system plays a role in the development of counterregulatory failure,
in part by enhancing central lactate production and therefore, the use of β-adrenergic
blockers may be a promising treatment to preserve the responses to hypoglycemia. Preliminary
data show that RH rats treated with low doses of the non-specific β-blocker, carvedilol,
during the induction of RH, required less exogenous glucose during the hypoglycemic clamp
compared to RH animals treated with vehicle. More importantly, reductions in VMH lactate
levels and significant improvements in the counterregulatory hormone responses to
hypoglycemia in the carvedilol-treated RH animals were observed.
Carvedilol is a third generation non-selective, vasodilating β-blocker, which is FDA-approved
for the treatment of congestive heart failure and hypertension. Carvedilol mainly blocks β2-
and β1-adrenergic receptors and some α1-adrenergic receptors. Due to its lipophilic nature,
carvedilol readily crosses the blood-brain barrier. As the brain is the primary target, this
beneficial pharmacokinetic property of carvedilol improves central nervous system
bioavailability, allowing lower doses to be used to deliver treatment to the brain. With
lower doses, the potential for side effects stemming from unnecessary exposure of peripheral
tissues to high levels of β-adrenergic blockade can be reduced. This study is designed to
evaluate the effectiveness of low-dose carvedilol treatment for 4 weeks as a treatment for
restoring the counterregulatory hormone responses to hypoglycemia and improve hypoglycemia
awareness in T1DM patients.
