Recurrent hypoglycemia leads to HAAF, with blunted counterregulatory hormone responses to subsequent hypoglycemic episodes. A recent report suggested inter-individual differences in susceptibility to HAAF (JCEM 102:3571, 2017). Since adrenergic receptor blockade prevents HAAF (Diabetes 60:602, 2011), we investigated to what extent the rises in plasma epinephrine (EPI) associated with hypoglycemia predict the development of HAAF. Healthy non-diabetic subjects (n=18, age 43±2years, BMI 25±1 kg/m2) underwent two 2-hour hypoglycemic clamp studies (nadir 54mg/dl; 0-2h and 4-6 h) on Day 1 followed by a third 2-hour hypoglycemic clamp on Day 2. Twelve subjects (67%) developed HAAF by the third episode, as defined by at least 20% reductions in peak EPI levels (peak EPI 1st vs. 3rd episode: HAAF subjects 1072±156 vs. 530±87pg/ml, p<0.001). Importantly, peak EPI levels during the 1st hypoglycemic episode were ∼83% higher in the subjects who developed HAAF compared to those who did not (p=0.02). To specifically define the role of EPI in the pathogenesis of HAAF, we challenged an additional seven non-diabetic subjects (age 32±4 years, BMI 25±1 kg/m2) with two 2-hour infusions of EPI (0.03 μg/kg/min;0-2h and 4-6 h) on Day 1 followed by 200-minute stepped hypoglycemic clamps (90, 80, 70 and 60 mg/dl, each for 50 minutes) on Day 2. Compared to saline, EPI infusion on Day 1 induced 40% and 28% reductions in epinephrine response to hypoglycemia at the 70 and 60 mg/dl glucose steps on Day 2, respectively (all p<0.05). There were parallel reductions in hypoglycemic symptoms (all p<0.05). Furthermore, the rate of glucose infusion was higher at all steps after EPI infusion (all p<0.05), consistent with a trend towards lower endogenous glucose production (6,6-D2-glucose). Thus, rises in EPI similar to those seen with hypoglycemia reproduce key features of HAAF in non-diabetic subjects. Marked inter-individual variability in EPI levels in response to hypoglycemia may explain why some people are more prone to develop HAAF. Disclosure E. Lontchi Yimagou: None. S. Aleksic: None. L. Upadhyay: None. S. Sharma: None. M. Carey: None. A. Goyal: None. J. You: None. R. Hulkower: None. S. Murthi: None. W.G. Mitchell: None. H. Shamoon: None. M. Hawkins: Other Relationship; Self; Novo Nordisk Inc. Funding American Diabetes Association (1-18-PMF-024 to E.L.Y.); National Institutes of Health (R01DK079974)
Diabetes among low BMI individuals has been recognized globally for over 60 years, and classified by WHO as malnutrition-related diabetes mellitus in 1985. Despite its prevalence in low and middle income countries, this condition has never been comprehensively studied. State of the art metabolic studies were performed in 20 South Indian men with Low BMI Diabetes (LD; BMI 18.3 ± 0.9 kg/m2), after excluding monogenic and immune diabetes, and visible pancreatic pathology. Other groups were studied: T1D, T2D, and nondiabetic subjects (BMI-matched to LD and T2D). Insulin secretion was assessed by C-peptide deconvolution following a mixed-meal tolerance test. Peripheral and hepatic insulin sensitivity were analyzed using tracer-based (6,6-deuterated glucose), stepped hyperinsulinemic-euglycemic pancreatic clamps following correction of glucose toxicity. LD subjects were distinct from both T1D and T2D. Insulin secretion was significantly lower in LD than in T2D subjects, yet higher than in T1D. LD subjects were more insulin sensitive than T2D; glucose uptake and endogenous glucose production did not differ from lean nondiabetic or T1D subjects. These comprehensive studies are the first to demonstrate that LD individuals are characterized by markedly impaired insulin secretion yet preserved insulin sensitivity. Thus, diabetes in low BMI individuals is a distinct entity that warrants further investigation. Disclosure E. Lontchi Yimagou: None. R. Das Gupta: None. S. Anoop: None. S. Kehlenbrink: None. J. Moy: None. A. Manavalan: None. P.M. Mathias: None. A. Goyal: None. M. Carey: None. D.T. Stein: None. N. Thomas: None. M. Hawkins: None. Funding National Institutes of Health (R01DK069861)
Repeated hypoglycemic episodes can cause HAAF, i.e., blunted counter-regulatory hormone responses. We have shown that activating opiate receptors can induce HAAF in healthy participants subjected to subsequent experimentally induced hypoglycemia. However, we have noted inter-individual variability in the development of HAAF. In our current study we evaluated the effect of blocking opioid receptors with intranasal naloxone in individuals at risk for HAAF. To identify people susceptible to HAAF, fourteen nondiabetic subjects (13M, age 43.4±8.0, BMI 25.5±2.19 kg/m2) underwent two 120-minute hyperinsulinemic hypoglycemic (nadir 54 mg/dl) clamp studies on Day 1 and a third hypoglycemic clamp study on Day 2. Nine individuals developed HAAF, defined as ≥20% reduction in average epinephrine (EPI) levels (90-120 minutes) between the first and third episodes of hypoglycemia (858 ±161 vs. 494±108 pg/ml, p=0.008). The HAAF-prone subjects underwent similar 3-episode hypoglycemic studies on two subsequent occasions with hourly placebo (randomized, double-blinded) or naloxone (4 mg) on Day 1. While average EPI levels declined from the first to the third hypoglycemic episode by 42% with placebo (p=0.01), levels did not differ with intranasal naloxone (p=0.67). Similarly, plasma glucagon levels decreased significantly from the first to the third hypoglycemic episode with placebo but were maintained with naloxone (Glucagon 1st vs. 3rd episode: Placebo 31.5±8.07 vs. 21.6±5.3 mg/ml, p=0.03; Naloxone 30.5±7.42 vs. 27.0±6.9 mg/ml, p=0.41). Naloxone did not alter plasma cortisol responses or hypoglycemic symptoms. This confirms previous reports of inter-individual variability in development of HAAF. Administration of intranasal naloxone during antecedent hypoglycemia prevented HAAF in susceptible individuals. Inhaled naloxone may offer a feasible approach to ameliorate HAAF in targeted individuals at risk for hypoglycemia-related adverse events. Disclosure A. Manavalan: None. P.M. Mathias: None. S. Aleksic: None. E. Lontchi Yimagou: None. M. Carey: None. J. Moy: None. T. Patel: None. B. Kuo: None. O. Sandu: None. H. Shamoon: None. M. Hawkins: None. Funding National Institutes of Health (R01DK079974)
OBJECTIVES/GOALS: Vitamin D [25(OH)D], known to have anti-inflammatory and anti-fibrotic effects in other tissues, may also impact adipose tissue. We designed parallel studies in humans and rodents to define the effects of vitamin D on adipose tissue inflammation and fibrosis, and on systemic insulin resistance. METHODS/STUDY POPULATION: We performed a randomized, double-blinded placebo-controlled trial to examine the effects of repleting vitamin D at to two levels (to >30 ng/ml and to > 50 ng/ml) in 25(OH)D-deficient (<20 ng/ml), insulin resistant, overweight-to-obese humans (n = 19). A comprehensive study of whole-body insulin action was undertaken with euglycemic stepped hyperinsulinemic clamp studies, both before (1st visit) and after administration of vitamin D or placebo (2nd visit and 3rd visit). Adipose tissue fibrosis and inflammation were quantified by ‘real-time’ rt-PCR and immunofluorescence. To determine whether vitamin D’s effects are mediated through adipocytes, we performed hyperinsulinemic clamp studies and adipose tissue analysis in an adipocyte-specific vitamin D receptor knockout (VDR KO) mouse model. RESULTS/ANTICIPATED RESULTS: 25(OH)D repletion (to >30 ng/ml) was associated with reductions in adipose tissue expression of inflammatory (0.6-0.7-fold decreased expression of TNF-α, IL-6, iNOS and PAI-1) and pro-fibrotic (0.4-0.8-fold decreased expression of TGF-β1, HiF1α, 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) (1.28 ± 0.20 vs 0.88 ± 0.18 mg/kg/min, p = 0.03). Compared to wild type (WT), VDR KO mice exhibited increased adipose tissue expression of several pro-inflammatory (Tnf-α, iNos, Pai-1, Mcp-1 and F4/80; 4-10 fold) and pro-fibrotic genes (Tgf-β1, Collagen VI, and Tsp1; 2-4 fold), in concert with hepatic insulin resistance (EGP 10 ± 3 vs 3 ± 2 mg/kg/min in WT, p = 0.021). DISCUSSION/SIGNIFICANCE OF IMPACT: Collectively, 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)D levels could have metabolic benefits in targeted individuals. CONFLICT OF INTEREST DESCRIPTION: N/A
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