The interplay between bone and heart health as reflected in medication effects: A narrative review.

There is mounting evidence of an association between osteoporosis and cardiovascular disease that extends beyond shared risk factors for these conditions. In turn, the medications used to treat each of these conditions can have effects that impact the other organ system: medications used in heart disease have the potential to affect bone health, while osteoporosis medications may modify cardiovascular health. While data in this subject area are limited by the paucity of large randomized controlled trials with bone mineral density or fracture risk as primary outcomes, this review explores the data available that can provide some insight into these reciprocal effects of medications on bone and heart health. Data on bone health effects of the loop and thiazide diuretics, beta blockers, calcium channel blockers, statins, warfarin, sodium-glucose cotransporter 2 inhibitors, metformin, and medications impacting the renin-angiotensin-aldosterone system are examined; the cardiovascular effects of osteoporosis therapies and vitamin D are also discussed. Importantly, while most data in this realm are inconclusive, recognizing the parallels between cardiovascular and bone disorders and how this is reflected in medication effects might prompt the clinician to consider the indirect impact of drug regimens when making therapeutic choices for patients with osteoporosis and heart disease.

Naltrexone for treatment of impaired awareness of hypoglycemia in type 1 diabetes: A randomized clinical trial.

AIMS: Impaired awareness of hypoglycemia (IAH) is a limiting factor in the treatment of type 1 diabetes (T1D) and is a challenging condition to reverse. The objective of this study was to test the hypothesis that naltrexone therapy in subjects with T1D and IAH will improve counterregulatory hormone response and recognition of hypoglycemia symptoms during hypoglycemia. METHODS: We performed a pilot randomized double blind trial of 4weeks of naltrexone therapy (n=10) or placebo (n=12) given orally in subjects with T1D and IAH. Outcome measures included hypoglycemia symptom scores, counterregulatory hormone levels and thalamic activation as measured by cerebral blood flow using MRI during experimental hypoglycemia in all subjects before and after 4weeks of intervention. RESULTS: After 4weeks of therapy with naltrexone or placebo, no significant differences in response to hypoglycemia were seen in any outcomes of interest within each group. CONCLUSIONS: In this small study, short-term treatment with naltrexone did not improve recognition of hypoglycemia symptoms or counterregulatory hormone response during experimental hypoglycemia in subjects with T1D and IAH. Whether this lack of effect is related to the small sample size or due to the dose, the advanced stage of study population or the drug itself should be the subject of future investigation.

Hypoglycemia-induced increases in thalamic cerebral blood flow are blunted in subjects with type 1 diabetes and hypoglycemia unawareness.

The thalamus has been found to be activated during the early phase of moderate hypoglycemia. Here, we tested the hypothesis that this region is less activated during hypoglycemia in subjects with type 1 diabetes (T1DM) and hypoglycemia unawareness relative to controls. Twelve controls (5 F/7 M, age 40 ± 14 years, body mass index 24.2 ± 2.7 kg/m(2)) and eleven patients (7 F/4 M, age 39 ± 13 years, body mass index 26.5 ± 4.4 kg/m(2)) with well-controlled T1DM (A1c 6.8 ± 0.4%) underwent a two-step hyperinsulinemic (2.0 mU/kg per minute) clamp. Cerebral blood flow (CBF) weighted images were acquired using arterial spin labeling to monitor cerebral activation in the midbrain regions. Blood glucose was first held at 95 mg/dL and then allowed to decrease to 50 mg/dL. The CBF image acquisition during euglycemia and hypoglycemia began within a few minutes of when the target blood glucose values were reached. Hypoglycemia unaware T1DM subjects displayed blunting of the physiologic CBF increase that occurs in the thalamus of healthy individuals during the early phase of moderate hypoglycemia. A positive correlation was observed between thalamic response and epinephrine response to hypoglycemia, suggesting that this region may be involved in the coordination of the counter regulatory response to hypoglycemia.

Brain glycogen content and metabolism in subjects with type 1 diabetes and hypoglycemia unawareness.

Supercompensated brain glycogen may contribute to the development of hypoglycemia unawareness in patients with type 1 diabetes by providing energy for the brain during periods of hypoglycemia. Our goal was to determine if brain glycogen content is elevated in patients with type 1 diabetes and hypoglycemia unawareness. We used in vivo (13)C nuclear magnetic resonance spectroscopy in conjunction with [1-(13)C]glucose administration in five patients with type 1 diabetes and hypoglycemia unawareness and five age-, gender-, and body mass index-matched healthy volunteers to measure brain glycogen content and metabolism. Glucose and insulin were administered intravenously over ∼51 hours at a rate titrated to maintain a blood glucose concentration of 7 mmol/L. (13)C-glycogen levels in the occipital lobe were measured at ∼5, 8, 13, 23, 32, 37, and 50 hours, during label wash-in and wash-out. Newly synthesized glycogen levels were higher in controls than in patients (P<0.0001) for matched average blood glucose and insulin levels, which may be due to higher brain glycogen content or faster turnover in controls. Metabolic modeling indicated lower brain glycogen content in patients than in controls (P=0.07), implying that glycogen supercompensation does not contribute to the development of hypoglycemia unawareness in humans with type 1 diabetes.

Noninvasive measurement of brain glycogen by nuclear magnetic resonance spectroscopy and its application to the study of brain metabolism.

Glycogen is the reservoir for glucose in the brain. Beyond the general agreement that glycogen serves as an energy source in the central nervous system, its exact role in brain energy metabolism has yet to be elucidated. Experiments performed in cell and tissue culture and animals have shown that glycogen content is affected by several factors, including glucose, insulin, neurotransmitters, and neuronal activation. The study of in vivo glycogen metabolism has been hindered by the inability to measure glycogen noninvasively, but, in the past several years, the development of a noninvasive localized (13) C nuclear magnetic resonance (NMR) spectroscopy method has allowed the study of glycogen metabolism in the conscious human. With this technique, (13) C-glucose is administered intravenously, and its incorporation into and washout from brain glycogen is tracked. One application of this method has been to the study of brain glycogen metabolism in humans during hypoglycemia: data have shown that mobilization of brain glycogen is augmented during hypoglycemia, and, after a single episode of hypoglycemia, glycogen synthesis rate is increased, suggesting that glycogen stores rebound to levels greater than baseline. Such studies suggest that glycogen may serve as a potential energy reservoir in hypoglycemia and may participate in the brain's adaptation to recurrent hypoglycemia and eventual development of hypoglycemia unawareness. Beyond this focused area of study, (13) C NMR spectroscopy has a broad potential for application in the study of brain glycogen metabolism and carries the promise of a better understanding of the role of brain glycogen in diabetes and other conditions.

Neuroendocrine responses to hypoglycemia.

The counterregulatory response to hypoglycemia is a complex and well-coordinated process. As blood glucose concentration declines, peripheral and central glucose sensors relay this information to central integrative centers to coordinate neuroendocrine, autonomic, and behavioral responses and avert the progression of hypoglycemia. Diabetes, both type 1 and type 2, can perturb these counterregulatory responses. Moreover, defective counterregulation in the setting of diabetes can progress to hypoglycemia unawareness. While the mechanisms that underlie the development of hypoglycemia unawareness are not completely known, possible causes include altered sensing of hypoglycemia by the brain and/or impaired coordination of responses to hypoglycemia. Further study is needed to better understand the intricacies of the counterregulatory response and the mechanisms contributing to the development of hypoglycemia unawareness.