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Article ; Online: Point: An alternative hypothesis for why exposure to static magnetic and electric fields treats type 2 diabetes.

Petersen, Kitt Falk / Rothman, Douglas L / Shulman, Gerald I

American journal of physiology. Endocrinology and metabolism

2021 Volume 320, Issue 5, Page(s) E999–E1000

MeSH term(s)	Diabetes Mellitus, Type 2/therapy ; Humans ; Magnetic Phenomena
Language	English
Publishing date	2021-04-12
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	603841-4
ISSN	1522-1555 ; 0193-1849
ISSN (online)	1522-1555
ISSN	0193-1849
DOI	10.1152/ajpendo.00657.2020
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Article ; Online: Reply to Carter et al.: An alternative hypothesis for why exposure to static magnetic and electric fields treats type 2 diabetes.

Petersen, Kitt Falk / Rothman, Douglas L / Shulman, Gerald I

American journal of physiology. Endocrinology and metabolism

2021 Volume 320, Issue 5, Page(s) E1003

MeSH term(s)	Diabetes Mellitus, Type 2/therapy ; Humans ; Magnetic Phenomena
Language	English
Publishing date	2021-04-12
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	603841-4
ISSN	1522-1555 ; 0193-1849
ISSN (online)	1522-1555
ISSN	0193-1849
DOI	10.1152/ajpendo.00120.2021
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Article ; Online: Ethnic and sex differences in hepatic lipid content and related cardiometabolic parameters in lean individuals

Kitt Falk Petersen / Sylvie Dufour / Fangyong Li / Douglas L. Rothman / Gerald I. Shulman

JCI Insight, Vol 7, Iss

2022 Volume 7

Abstract: Background Nonalcoholic fatty liver affects 25% to 30% of the US and European populations; is associated with insulin resistance (IR), type 2 diabetes, and increased cardiovascular risk; and is defined by hepatic triglyceride (HTG) content greater than 5. ...

Abstract	Background Nonalcoholic fatty liver affects 25% to 30% of the US and European populations; is associated with insulin resistance (IR), type 2 diabetes, and increased cardiovascular risk; and is defined by hepatic triglyceride (HTG) content greater than 5.56%. However, it is unknown whether HTG content less than 5.56% is associated with cardiometabolic risk factors and whether there are ethnic (Asian Indian, AI, versus non-AI) and/or sex differences in these parameters in lean individuals.Methods We prospectively recruited 2331 individuals and measured HTG, using 1H magnetic resonance spectroscopy, and plasma concentrations of triglycerides, total cholesterol, LDL-cholesterol, HDL-cholesterol, and uric acid. Insulin sensitivity was assessed using Homeostatic Model Assessment of Insulin Resistance and the Matsuda Insulin Sensitivity Index.Results The 95th percentile for HTG in lean non-AI individuals was 1.85%. Plasma insulin, triglycerides, total cholesterol, LDL-cholesterol, and uric acid concentrations were increased and HDL-cholesterol was decreased in individuals with HTG content > 1.85% and ≤ 5.56% compared with those individuals with HTG content ≤ 1.85%, and these altered parameters were associated with increased IR. Mean HTG was lower in lean non-AI women compared with lean non-AI men, whereas lean AI men and women had a 40% to 100% increase in HTG when compared with non-AI men and women, which was associated with increased cardiometabolic risk factors.Conclusion We found that the 95th percentile of HTG in lean non-AI individuals was 1.85% and that HTG concentrations above this threshold were associated with IR and cardiovascular risk factors. Premenopausal women were protected from these changes whereas young, lean AI men and women manifested increased HTG content and associated cardiometabolic risk factors.Funding Grants from the United States Department of Health and Human Resources (NIH/National Institute of Diabetes and Digestive and Kidney Diseases): R01 DK113984, P30 DK45735, U24 DK59635, and UL1 ...
Keywords	Hepatology ; Metabolism ; Medicine ; R
Subject code	610
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Effect of Burosumab on Muscle Function and Strength, and Rates of ATP Synthesis in Skeletal Muscle in Adults With XLH.

Insogna, Karl L / Sullivan, Rebecca / Parziale, Stephen / Deng, Yanhong / Carrano, Diana / Simpson, Christine / Dufour, Sylvie / Carpenter, Thomas / Petersen, Kitt Falk

The Journal of clinical endocrinology and metabolism

2023 Volume 109, Issue 3, Page(s) e1061–e1071

Abstract: Context: In clinical trials, burosumab ameliorates symptoms of pain, fatigue, and stiffness and improves performance on certain muscle function studies in patients with X-linked hypophosphatemia (XLH).: Objective: This work aimed to determine if ... ...

Abstract	Context: In clinical trials, burosumab ameliorates symptoms of pain, fatigue, and stiffness and improves performance on certain muscle function studies in patients with X-linked hypophosphatemia (XLH). Objective: This work aimed to determine if burosumab increases adenosine triphosphate (ATP) synthesis in skeletal muscle of treatment-naive adults with XLH, and if so, whether that correlates with improved muscle function. Methods: Ten untreated, symptomatic adults with XLH had ATP synthesis rates measured in the right calf using the 31P magnetic resonance spectroscopy saturation transfer technique. Baseline muscle function tests and symptoms of pain, fatigue, stiffness, and lower-extremity joint pain were quantified. All participants were treated with burosumab, 1 mg/kg every 4 weeks for 12 weeks. ATP synthesis rates and muscle function tests were repeated 2 weeks ("peak") and 4 weeks ("trough") after the third dose of burosumab. Results: All symptoms improved with treatment. Performance on the 6-Minute Walk Test (6MWT) and Sit to Stand (STS) tests also improved. Muscle strength and ATP synthesis rates did not change over the 3 months of the study. When individuals whose performances on the 6MWT and STS test were at or better than the median outcome for those tests were compared to those whose outcomes were below the median, no difference was observed in the rate of change in ATP synthesis. Intracellular muscle concentrations of phosphate were normal. Conclusion: The improvement in the 6MWT and STS test without changes in muscle strength or ATP synthesis rates suggests that reductions in pain, fatigue, and stiffness may partly explain the improved performance. Intracellular phosphate in skeletal muscle is insulated from hypophosphatemia in XLH.
MeSH term(s)	Adult ; Humans ; Antibodies, Monoclonal/therapeutic use ; Familial Hypophosphatemic Rickets/diagnosis ; Adenosine Triphosphate ; Muscle, Skeletal ; Polyphosphates/therapeutic use ; Pain/drug therapy ; Leg ; Fatigue/drug therapy ; Antibodies, Monoclonal, Humanized
Chemical Substances	burosumab (G9WJT6RD29) ; Antibodies, Monoclonal ; Adenosine Triphosphate (8L70Q75FXE) ; triphosphoric acid (NU43IAG5BC) ; Polyphosphates ; Antibodies, Monoclonal, Humanized
Language	English
Publishing date	2023-11-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	3029-6
ISSN	1945-7197 ; 0021-972X
ISSN (online)	1945-7197
ISSN	0021-972X
DOI	10.1210/clinem/dgad642
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Article ; Online: Ethnic and sex differences in hepatic lipid content and related cardiometabolic parameters in lean individuals.

Petersen, Kitt Falk / Dufour, Sylvie / Li, Fangyong / Rothman, Douglas L / Shulman, Gerald I

JCI insight

2022 Volume 7, Issue 7

Abstract: BackgroundNonalcoholic fatty liver affects 25% to 30% of the US and European populations; is associated with insulin resistance (IR), type 2 diabetes, and increased cardiovascular risk; and is defined by hepatic triglyceride (HTG) content greater than 5 ... ...

Abstract	BackgroundNonalcoholic fatty liver affects 25% to 30% of the US and European populations; is associated with insulin resistance (IR), type 2 diabetes, and increased cardiovascular risk; and is defined by hepatic triglyceride (HTG) content greater than 5.56%. However, it is unknown whether HTG content less than 5.56% is associated with cardiometabolic risk factors and whether there are ethnic (Asian Indian, AI, versus non-AI) and/or sex differences in these parameters in lean individuals.MethodsWe prospectively recruited 2331 individuals and measured HTG, using 1H magnetic resonance spectroscopy, and plasma concentrations of triglycerides, total cholesterol, LDL-cholesterol, HDL-cholesterol, and uric acid. Insulin sensitivity was assessed using Homeostatic Model Assessment of Insulin Resistance and the Matsuda Insulin Sensitivity Index.ResultsThe 95th percentile for HTG in lean non-AI individuals was 1.85%. Plasma insulin, triglycerides, total cholesterol, LDL-cholesterol, and uric acid concentrations were increased and HDL-cholesterol was decreased in individuals with HTG content > 1.85% and ≤ 5.56% compared with those individuals with HTG content ≤ 1.85%, and these altered parameters were associated with increased IR. Mean HTG was lower in lean non-AI women compared with lean non-AI men, whereas lean AI men and women had a 40% to 100% increase in HTG when compared with non-AI men and women, which was associated with increased cardiometabolic risk factors.ConclusionWe found that the 95th percentile of HTG in lean non-AI individuals was 1.85% and that HTG concentrations above this threshold were associated with IR and cardiovascular risk factors. Premenopausal women were protected from these changes whereas young, lean AI men and women manifested increased HTG content and associated cardiometabolic risk factors.FundingGrants from the United States Department of Health and Human Resources (NIH/National Institute of Diabetes and Digestive and Kidney Diseases): R01 DK113984, P30 DK45735, U24 DK59635, and UL1 RR024139; and the Novo Nordisk Foundation (NNF18CC0034900).
MeSH term(s)	Cardiovascular Diseases ; Cholesterol, HDL ; Cholesterol, LDL ; Diabetes Mellitus, Type 2 ; Female ; Humans ; Insulin Resistance ; Male ; Sex Characteristics ; Triglycerides ; Uric Acid
Chemical Substances	Cholesterol, HDL ; Cholesterol, LDL ; Triglycerides ; Uric Acid (268B43MJ25)
Language	English
Publishing date	2022-04-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.157906
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Article ; Online: Mitochondrial Dysfunction, Insulin Resistance, and Potential Genetic Implications.

Sangwung, Panjamaporn / Petersen, Kitt Falk / Shulman, Gerald I / Knowles, Joshua W

Endocrinology

2020 Volume 161, Issue 4

Abstract: Insulin resistance (IR) is fundamental to the development of type 2 diabetes (T2D) and is present in most prediabetic (preDM) individuals. Insulin resistance has both heritable and environmental determinants centered on energy storage and metabolism. ... ...

Abstract	Insulin resistance (IR) is fundamental to the development of type 2 diabetes (T2D) and is present in most prediabetic (preDM) individuals. Insulin resistance has both heritable and environmental determinants centered on energy storage and metabolism. Recent insights from human genetic studies, coupled with comprehensive in vivo and ex vivo metabolic studies in humans and rodents, have highlighted the critical role of reduced mitochondrial function as a predisposing condition for ectopic lipid deposition and IR. These studies support the hypothesis that reduced mitochondrial function, particularly in insulin-responsive tissues such as skeletal muscle, white adipose tissue, and the liver, is inextricably linked to tissue and whole body IR through the effects on cellular energy balance. Here we discuss these findings as well as address potential mechanisms that serve as the nexus between mitochondrial malfunction and IR.
MeSH term(s)	Adipose Tissue, White/metabolism ; Diabetes Mellitus, Type 2/genetics ; Diabetes Mellitus, Type 2/metabolism ; Humans ; Insulin Resistance/physiology ; Lipid Metabolism/physiology ; Liver/metabolism ; Mitochondria/genetics ; Mitochondria/metabolism ; Muscle, Skeletal/metabolism ; Prediabetic State/genetics ; Prediabetic State/metabolism
Language	English
Publishing date	2020-02-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	427856-2
ISSN	1945-7170 ; 0013-7227
ISSN (online)	1945-7170
ISSN	0013-7227
DOI	10.1210/endocr/bqaa017
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Article ; Online: Lysophosphatidic acid triggers inflammation in the liver and white adipose tissue in rat models of 1-acyl-sn-glycerol-3-phosphate acyltransferase 2 deficiency and overnutrition.

Sakuma, Ikki / Gaspar, Rafael C / Luukkonen, Panu K / Kahn, Mario / Zhang, Dongyan / Zhang, Xuchen / Murray, Sue / Golla, Jaya Prakash / Vatner, Daniel F / Samuel, Varman T / Petersen, Kitt Falk / Shulman, Gerald I

Proceedings of the National Academy of Sciences of the United States of America

2023 Volume 120, Issue 52, Page(s) e2312666120

Abstract: AGPAT2 (1-acyl-sn-glycerol-3-phosphate-acyltransferase-2) converts lysophosphatidic acid (LPA) into phosphatidic acid (PA), and mutations of ... ...

Abstract	AGPAT2 (1-acyl-sn-glycerol-3-phosphate-acyltransferase-2) converts lysophosphatidic acid (LPA) into phosphatidic acid (PA), and mutations of the
MeSH term(s)	Male ; Rats ; Animals ; Acyltransferases/metabolism ; Glycerol ; 1-Acylglycerol-3-Phosphate O-Acyltransferase/genetics ; 1-Acylglycerol-3-Phosphate O-Acyltransferase/metabolism ; Rats, Sprague-Dawley ; Lipodystrophy/genetics ; Fatty Liver ; Adipose Tissue, White/metabolism ; Phosphatidic Acids ; Inflammation ; Overnutrition ; Phosphates
Chemical Substances	Acyltransferases (EC 2.3.-) ; lysophosphatidic acid (PG6M3969SG) ; Glycerol (PDC6A3C0OX) ; 1-Acylglycerol-3-Phosphate O-Acyltransferase (EC 2.3.1.51) ; Phosphatidic Acids ; Phosphates
Language	English
Publishing date	2023-12-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2312666120
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Article ; Online: Inhibition of

Luukkonen, Panu K / Sakuma, Ikki / Gaspar, Rafael C / Mooring, Meghan / Nasiri, Ali / Kahn, Mario / Zhang, Xian-Man / Zhang, Dongyan / Sammalkorpi, Henna / Penttilä, Anne K / Orho-Melander, Marju / Arola, Johanna / Juuti, Anne / Zhang, Xuchen / Yimlamai, Dean / Yki-Järvinen, Hannele / Petersen, Kitt Falk / Shulman, Gerald I

Proceedings of the National Academy of Sciences of the United States of America

2023 Volume 120, Issue 4, Page(s) e2217543120

Abstract: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, in which prognosis is determined by liver fibrosis. A common variant in hydroxysteroid 17-beta dehydrogenase 13 ( ...

Abstract	Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, in which prognosis is determined by liver fibrosis. A common variant in hydroxysteroid 17-beta dehydrogenase 13 (
MeSH term(s)	Animals ; Humans ; Mice ; Liver/metabolism ; Liver Cirrhosis/pathology ; Non-alcoholic Fatty Liver Disease/pathology ; Pyrimidines/pharmacology ; Pyrimidines/metabolism
Chemical Substances	pyrimidine (K8CXK5Q32L) ; Pyrimidines ; HSD17B13 protein, human (EC 1.1.-.-)
Language	English
Publishing date	2023-01-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2217543120
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Article ; Online: The PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans.

Luukkonen, Panu K / Porthan, Kimmo / Ahlholm, Noora / Rosqvist, Fredrik / Dufour, Sylvie / Zhang, Xian-Man / Lehtimäki, Tiina E / Seppänen, Wenla / Orho-Melander, Marju / Hodson, Leanne / Petersen, Kitt Falk / Shulman, Gerald I / Yki-Järvinen, Hannele

Cell metabolism

2023 Volume 35, Issue 11, Page(s) 1887–1896.e5

Abstract: The PNPLA3 I148M variant is the major genetic risk factor for all stages of fatty liver disease, but the underlying pathophysiology remains unclear. We studied the effect of this variant on hepatic metabolism in homozygous carriers and non-carriers under ...

Abstract	The PNPLA3 I148M variant is the major genetic risk factor for all stages of fatty liver disease, but the underlying pathophysiology remains unclear. We studied the effect of this variant on hepatic metabolism in homozygous carriers and non-carriers under multiple physiological conditions with state-of-the-art stable isotope techniques. After an overnight fast, carriers had higher plasma β-hydroxybutyrate concentrations and lower hepatic de novo lipogenesis (DNL) compared to non-carriers. After a mixed meal, fatty acids were channeled toward ketogenesis in carriers, which was associated with an increase in hepatic mitochondrial redox state. During a ketogenic diet, carriers manifested increased rates of intrahepatic lipolysis, increased plasma β-hydroxybutyrate concentrations, and decreased rates of hepatic mitochondrial citrate synthase flux. These studies demonstrate that homozygous PNPLA3 I148M carriers have hepatic mitochondrial dysfunction leading to reduced DNL and channeling of carbons to ketogenesis. These findings have implications for understanding why the PNPLA3 variant predisposes to progressive liver disease.
MeSH term(s)	Humans ; Lipogenesis/genetics ; 3-Hydroxybutyric Acid/metabolism ; Liver/metabolism ; Non-alcoholic Fatty Liver Disease/metabolism ; Mitochondria/metabolism ; Genetic Predisposition to Disease
Chemical Substances	3-Hydroxybutyric Acid (TZP1275679)
Language	English
Publishing date	2023-10-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2176834-1
ISSN	1932-7420 ; 1550-4131
ISSN (online)	1932-7420
ISSN	1550-4131
DOI	10.1016/j.cmet.2023.10.008
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Article ; Online: The effects of increased acetate turnover on glucose-induced insulin secretion in lean and obese humans.

Petersen, Kitt Falk / Impellizeri, Anne / Cline, Gary W / Shulman, Gerald I

Journal of clinical and translational science

2019 Volume 3, Issue 1, Page(s) 18–20

Abstract: Introduction: Increased endogenous acetate production (Ra) in rodents has been shown to activate the parasympathetic nervous system and thereby promote increased glucose-stimulated insulin secretion (GSIS), increased ghrelin secretion, hyperphagia and ... ...

Abstract	Introduction: Increased endogenous acetate production (Ra) in rodents has been shown to activate the parasympathetic nervous system and thereby promote increased glucose-stimulated insulin secretion (GSIS), increased ghrelin secretion, hyperphagia and obesity. Aim: To examine whether rates of acetate turnover are different in lean versus obese humans and whether increased acetate turnover promotes increased GSIS and increased ghrelin secretion in humans. Methods: Basal acetate Ra was measured following an overnight fast in lean (BMI: 21.3 ± 1.1 Kg/m Results: Basal acetate Ra was 30% higher in the lean compared to the obese subjects (257 ± 27 vs. 173 ± 18 μmol/min; Conclusion: Rates of endogenous acetate turnover are ∼30% higher in the lean subjects compared to the obese subjects, and increasing plasma acetate turnover does not promote increased GSIS or ghrelin secretion in either group.
Language	English
Publishing date	2019-07-26
Publishing country	England
Document type	Journal Article
ISSN	2059-8661
ISSN (online)	2059-8661
DOI	10.1017/cts.2018.342
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