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Plasma Epinephrine Contributes to the Development of Experimental Hypoglycemia-Associated Autonomic Failure

Lontchi-Yimagou, Eric; Aleksic, Sandra; Hulkower, Raphael; Gospin, Rebekah; Goyal, Akankasha; Kuo, Bryan; Mitchell, William G; You, Jee Young; Upadhyay, Laxmi; Carey, Michelle; Sandu, Oana A; Gabriely, Ilan; Shamoon, Harry; Hawkins, Meredith
BACKGROUND:Recurrent hypoglycemia blunts counter-regulatory responses to subsequent hypoglycemic episodes, a syndrome known as hypoglycemia-associated autonomic failure (HAAF). Since adrenergic receptor blockade has been reported to prevent HAAF, we investigated whether the hypoglycemia-associated rise in plasma epinephrine contributes to pathophysiology and reported interindividual differences in susceptibility to HAAF. METHODS:To assess the role of hypoglycemia-associated epinephrine responses in the susceptibility to HAAF, 24 adult nondiabetic subjects underwent two 2-hour hyperinsulinemic hypoglycemic clamp studies (nadir 54 mg/dL; 0-2 hours and 4-6 hours) on Day 1, followed by a third identical clamp on Day 2. We challenged an additional 7 subjects with two 2-hour infusions of epinephrine (0.03 μg/kg/min; 0-2 hours and 4-6 hours) vs saline on Day 1 followed by a 200-minute stepped hypoglycemic clamp (90, 80, 70, and 60 mg/dL) on Day 2. RESULTS:Thirteen out of 24 subjects developed HAAF, defined by ≥20% reduction in average epinephrine levels during the final 30 minutes of the third compared with the first hypoglycemic episode (P < 0.001). Average epinephrine levels during the final 30 minutes of the first hypoglycemic episode were 2.3 times higher in subjects who developed HAAF compared with those who did not (P = 0.006).Compared to saline, epinephrine infusion on Day 1 reduced the epinephrine responses by 27% at the 70 and 60 mg/dL glucose steps combined (P = 0.04), with a parallel reduction in hypoglycemic symptoms (P = 0.03) on Day 2. CONCLUSIONS:Increases in plasma epinephrine reproduce key features of HAAF in nondiabetic subjects. Marked interindividual variability in epinephrine responses to hypoglycemia may explain an individual's susceptibility to developing HAAF.
PMID: 32915987
ISSN: 1945-7197
CID: 4614732

Liver insulin sensitizing effects of vitamin d mediated through reduced adipose tissue inflammation and fibrosis [Meeting Abstract]

Yimagou, E L; Kang, S; Zhang, K; Goyal, A; You, J Y; Kishore, P; Rosen, E; Hawkins, M
Purpose of study Since vitamin D (25(OH)D) has anti-inflammatory and anti-fibrotic effects, expression of its receptor in adipocytes and macrophages suggests that 25(OH)D signaling could mediate paracrine effects within adipose tissue and improve insulin resistance. We assessed the effects of vitamin D on adipose tissue inflammation and fibrosis, and on systemic insulin resistance. Methods used We performed a randomized, double-blinded placebo-controlled trial to examine the effects of repleting vitamin D levels to >30 ng/ml in 25(OH)D-deficient (<20 ng/ ml), insulin resistant, obese humans (n=19). Insulin sensitivity was assessed with stepped euglycemic hyperinsulinemic clamps before (1st visit) and after administration of vitamin D or placebo (2nd visit). Adipose tissue fibrosis and inflammation were quantified in subcutaneous abdominal adipose tissue. To determine whether vitamin D's effects are mediated through adipocytes, we performed hyperinsulinemic clamps and adipose tissue analysis in an adipocyte-specific vitamin D receptor knockout (VDR KO) mouse model. Summary of results 25(OH)D repletion was associated with reductions in adipose tissue gene expression of inflammatory (0.6-0.7-fold decreased expression of TNF-alpha, IL-6, iNOS, PAI- 1) and pro-fibrotic (0.4-0.8-fold decreased expression of TGFbeta1, HiF1alpha, Collagen I, V, VI and MMP7) factors, decreased collagen VI immunofluorescence (p=0.02) and improved hepatic insulin sensitivity in humans, with suppression of endogenous glucose production(EGP)(p=0.03)(figure 1a). Compared to wild type (WT), adipose-specific VDR KO mice exhibited increased adipose tissue expression of several pro-inflammatory (Tnf-alpha, iNos, Pai-1, Mcp-1, F4/80; 4-10 fold) and pro-fibrotic genes (Tgf-beta1, Collagen VI, Tsp1; 2-4 fold) in concert with hepatic insulin resistance (p=0.021)(figure 1b). There were no changes in glucose uptake in either humans or mice. Conclusions These complementary human and rodent studies establish a beneficial role of vitamin D to improve hepatic insulin resistance, likely by restraining adipose tissue inflammation and fibrosis. Thus, normalizing 25(OH)Dlevels could have metabolic benefits in targeted individuals. (Figure Presented)
EMBASE:628088803
ISSN: 1708-8267
CID: 3944492

Abnormally normal 1,25-dihydroxyvitamin d [1,25(OH)2D] with hypercalcemia in the setting of granulomatous disease [Meeting Abstract]

Vallejo, F A; Natter, M; Goyal, A
Introduction: Hypercalcemia is a rare finding in tuberculosis (TB). The prevalence varies from 2% to 48%. Elevation of 1,25(OH)2D is characteristic in hypercalcemia due to granulomatous disorders such as TB, but this has not been a consistent finding. We present a case of hypercalcemia due to TB with a normal 1,25(OH)2D. Case Presentation: A 35 year-old woman with newly diagnosed HIV was admitted for treatment of multidrug resistant granulomatous TB present in lungs, pleura and genitourinary tract. One week after admission, increase in serum calcium was noted with a peak at 14.2mg/dL. Further work-up showed normal 1,25(OH)2D 55pg/mL, 25(OH)D 17ng/mL, PTH 6.7pg/mL, 24h urine calcium 256 mg/24h, and normal PTHrP, thyroid function tests, serum and urine protein electrophoresis, morning cortisol and serum creatinine. Physical exam was remarkable for dry skin and mucosa, and reduced breath sounds in lung fields. Intravenous hydration was started, but the serum calcium continued to increase. At this point, prednisone 20 mg daily was started. Serum calcium has decreased to less than 11mg/dl and 1,25(OH)2D to 41 pg/mL after two weeks of therapy. Discussion: Classic laboratory findings in hypercalcemia due to granulomatous diseases are suppressed PTH, elevated 1,25(OH)2D and normal 25(OH)D. The reason behind increased 1,25(OH)2D levels in TB is the generation of cathelicidins to potentiate macrophage killing of Mycobacterium tuberculosis. Lymphocytes, monocytes, and macrophages outside of the granuloma, as well as pulmonary alveolar macrophages (PAMs) within the granuloma, drive the metabolism of 25(OH)D to 1,25(OH)2D via PAM 25(OH)D3-1 alpha hydroxylase. However, Sullivan et al (1987) highlighted four cases of active TB with low 1,25(OH)2D. Parker et al (1984) and Ryzen et al (1985), reported a case of coccidioidomycosis and leprosy respectively, both with low 1,25(OH)2D. Falk et al (2007) described a case of sarcoidosis with normal levels of 1,25(OH)2D. There are potential causes of inappropriately normal 1,25(OH)2D. One possibility is an inappropriately low baseline 1,25(OH)2D with an increase to normal values when the disease is active. A second potential cause is rifampin or isoniazid induced hypocalcitriolemia. A third possibility is a decrease in Vitamin D Binding Protein (
EMBASE:623114426
ISSN: 0163-769x
CID: 3211382

Opioid Receptor Activation Impairs Hypoglycemic Counterregulation in Humans

Carey, Michelle; Gospin, Rebekah; Goyal, Akankasha; Tomuta, Nora; Sandu, Oana; Mbanya, Armand; Lontchi-Yimagou, Eric; Hulkower, Raphael; Shamoon, Harry; Gabriely, Ilan; Hawkins, Meredith
Although intensive glycemic control improves outcomes in type 1 diabetes mellitus, iatrogenic hypoglycemia limits its attainment. Recurrent and/or antecedent hypoglycemia causes blunting of protective counterregulatory responses, known as Hypoglycemia-Associated Autonomic Failure (HAAF). To determine whether and how opioid receptor activation induces HAAF in humans, twelve healthy, non-diabetic subjects (7M, age 32.3 +/- 2.2 yr, BMI 25.1 +/- 1.0 kg/m2) participated in two study protocols in random order over two consecutive days. On day 1 subjects received two 120-minute infusions of either saline (SAL) or morphine (MOR, 0.1mug/kg/min), separated by a 120-minute break (all euglycemic). On day 2 subjects underwent stepped hypoglycemic clamps (nadir 60mg/dL) with evaluation of counterregulatory hormonal responses, endogenous glucose production (EGP, using 6,6-D2-glucose), and hypoglycemic symptoms. Morphine induced a approximately 30% reduction in plasma epinephrine response together with reduced EGP and hypoglycemia-associated symptoms on day 2. Therefore, we report the first studies in humans demonstrating that pharmacologic opioid receptor activation induces some of the clinical and biochemical features of HAAF, thus elucidating the individual roles of various receptors involved in HAAF's development and suggesting novel pharmacologic approaches for safer intensive glycemic control in T1DM.
PMCID:5652610
PMID: 28860128
ISSN: 1939-327x
CID: 2677212

Pancreatic Cancer Heralded by Worsening Glycemic Control: A Report of Two Cases

Desai, Dimpi; Rao, Devika; Sukrithan, Vineeth; Weinstein, Eleanor; Goyal, Akankasha; Schubart, Ulrich
Pancreatic ductal adenocarcinoma is the third leading cause of cancer-related death in the United States. Since it is usually diagnosed at an advanced stage, its prognosis remains poor. The initial presentation varies according to the tumor location. The most common presenting signs are weight loss, jaundice, and pain. Several epidemiological, clinical, and experimental studies over the past 2 decades have shown that long-standing diabetes is a modest risk factor for pancreatic cancer. However, new-onset diabetes has also been observed to be an early manifestation of pancreatic cancer. We report 2 cases where worsening glycemic control led to the diagnosis of pancreatic cancer.
PMCID:5468763
PMID: 28634594
ISSN: 2324-7096
CID: 2677172

VITAMIN D REPLETION REDUCES ADIPOSE TISSUE FIBROSIS AND IMPROVES INSULIN SENSITIVITY [Meeting Abstract]

You, Jee Young; Lontchi-Yimagou, Eric; Jain, Swati; Zhang, Kehao Y; Goyal, Akankasha; Kishore, Preeti; Hawkins, Meredith
ISI:000399374600012
ISSN: 1708-8267
CID: 2677302

IMPACT OF OPIOID AND ADRENERGIC RECEPTOR ACTIVATION ON HYPOGLYCEMIA-ASSOCIATED AUTONOMIC FAILURE (HAAF) [Meeting Abstract]

Lontchi-Yimagou, Eric; Gospin, Rebekah; Hulkower, Raphael; Goyal, Akankasha; Carey, Michelle; Sandu, Oana A; Tomuta, Nora; Shamoon, Harry; Gabriely, Ilan; Hawkins, Meredith
ISI:000399374600014
ISSN: 1708-8267
CID: 2677202

Central Regulation of Glucose Production May Be Impaired in Type 2 Diabetes

Esterson, Yonah B; Carey, Michelle; Boucai, Laura; Goyal, Akankasha; Raghavan, Pooja; Zhang, Kehao; Mehta, Deeksha; Feng, Daorong; Wu, Licheng; Kehlenbrink, Sylvia; Koppaka, Sudha; Kishore, Preeti; Hawkins, Meredith
The challenges of achieving optimal glycemic control in type 2 diabetes highlight the need for new therapies. Inappropriately elevated endogenous glucose production (EGP) is the main source of hyperglycemia in type 2 diabetes. Because activation of central ATP-sensitive potassium (KATP) channels suppresses EGP in nondiabetic rodents and humans, this study examined whether type 2 diabetic humans and rodents retain central regulation of EGP. The KATP channel activator diazoxide was administered in a randomized, placebo-controlled crossover design to eight type 2 diabetic subjects and seven age- and BMI-matched healthy control subjects. Comprehensive measures of glucose turnover and insulin sensitivity were performed during euglycemic pancreatic clamp studies following diazoxide and placebo administration. Complementary rodent clamp studies were performed in Zucker Diabetic Fatty rats. In type 2 diabetic subjects, extrapancreatic KATP channel activation with diazoxide under fixed hormonal conditions failed to suppress EGP, whereas matched control subjects demonstrated a 27% reduction in EGP (P = 0.002) with diazoxide. Diazoxide also failed to suppress EGP in diabetic rats. These results suggest that suppression of EGP by central KATP channel activation may be lost in type 2 diabetes. Restoration of central regulation of glucose metabolism could be a promising therapeutic target to reduce hyperglycemia in type 2 diabetes.
PMCID:5001178
PMID: 27207526
ISSN: 1939-327x
CID: 2677182

Hypoglycemia-Associated Autonomic Failure (HAAF) Is Induced by Opioid but Not Adrenergic Receptor Activation [Meeting Abstract]

Gospin, Rebekah; Tiwari, Akankasha; Carey, Michelle; Tomuta, Nora; Shamoon, Harry; Gabriely, Ilan; Hawkins, Meredith; Mbanya, Armand
ISI:000398372800150
ISSN: 1939-327x
CID: 2677192

Insulin Secretion Defects in Low Body Mass Index (BMI) Diabetes [Meeting Abstract]

Dasgupta, Riddhi; Goyal, Akankasha; Wickramanayake, Anneka; Kocherlakota, Chaithanya Murthy; Thomas, Nihal; Hawkins, Meredith
ISI:000398372800370
ISSN: 1939-327x
CID: 2677282