Effects of Insulin Therapy on Myocardial Lipid Content and Cardiac Geometry in Patients with Type-2 Diabetes Mellitus

Aims/Hypothesis Recent evidence suggests a link between myocardial steatosis and diabetic cardiomyopathy. Insulin, as a lipogenic and growth-promoting hormone, might stimulate intramyocardial lipid (MYCL) deposition and hypertrophy. Therefore, the aim of the present study was to investigate the short-term effects of insulin therapy (IT) on myocardial lipid content and morphology in patients with T2DM. Methods Eighteen patients with T2DM were recruited (age 56±2 years; HbA1c: 10.5±0.4%). In 10 patients with insufficient glucose control under oral medication IT was initiated due to secondary failure of oral glucose lowering therapy (IT-group), while 8 individuals did not require additional insulin substitution (OT-group). In order to assess MYCL and intrahepatic lipid (IHLC) content as well as cardiac geometry and function magnetic resonance spectroscopy (MRS) and imaging (MRI) examinations were performed at baseline (IT and OT) and 10 days after initiation of IT. Follow up measurements took place 181±49 days after IT. Results Interestingly, basal MYCLs were 50% lower in IT- compared to OT-group (0.41±0.12 vs. 0.80±0.11% of water signal; p = 0.034). After 10 days of IT, an acute 80%-rise in MYCL (p = 0.008) was observed, while IHLC did not change. Likewise, myocardial mass (+13%; p = 0.004), wall thickness in end-diastole (+13%; p = 0.030) and concentricity, an index of cardiac remodeling, increased (+28%; p = 0.026). In the long-term MYCL returned to baseline, while IHCL significantly decreased (−31%; p = 0.000). No acute changes in systolic left ventricular function were observed. Conclusions/Interpretation The initiation of IT in patients with T2DM was followed by an acute rise in MYCL concentration and myocardial mass.

[1]  P. Iozzo,et al.  Trimetazidine reduces endogenous free fatty acid oxidation and improves myocardial efficiency in obese humans. , 2012, Cardiovascular therapeutics.

[2]  G. Reiter,et al.  Short-Term Hyperinsulinemia and Hyperglycemia Increase Myocardial Lipid Content in Normal Subjects , 2012, Diabetes.

[3]  G. Reiter,et al.  Insulin resistance is not associated with myocardial steatosis in women , 2011, Diabetologia.

[4]  L. Bilet,et al.  Exercise-induced modulation of cardiac lipid content in healthy lean young men , 2010, Basic Research in Cardiology.

[5]  Ewald Moser,et al.  Non-invasive assessment of hepatic fat accumulation in chronic hepatitis C by 1H magnetic resonance spectroscopy. , 2010, European journal of radiology.

[6]  C. Fox,et al.  Relations of Insulin Resistance and Glycemic Abnormalities to Cardiovascular Magnetic Resonance Measures of Cardiac Structure and Function: The Framingham Heart Study , 2010, Circulation. Cardiovascular imaging.

[7]  E. Abel,et al.  Lipotoxicity in the heart. , 2010, Biochimica et biophysica acta.

[8]  P. Iozzo,et al.  Contribution of glucose tolerance and gender to cardiac adiposity. , 2009, The Journal of clinical endocrinology and metabolism.

[9]  Louis Hue,et al.  The Randle cycle revisited: a new head for an old hat. , 2009, American journal of physiology. Endocrinology and metabolism.

[10]  S. Schinner,et al.  Effects of Intensive Glucose Lowering in Type 2 Diabetes , 2009 .

[11]  Jeroen J. Bax,et al.  Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus. , 2008, Journal of the American College of Cardiology.

[12]  Jeroen J. Bax,et al.  Short-term flexibility of myocardial triglycerides and diastolic function in patients with type 2 diabetes mellitus. , 2008, American journal of physiology. Endocrinology and metabolism.

[13]  H. Lamb,et al.  Progressive caloric restriction induces dose-dependent changes in myocardial triglyceride content and diastolic function in healthy men. , 2008, The Journal of clinical endocrinology and metabolism.

[14]  Jeroen J. Bax,et al.  Metabolic imaging of myocardial triglyceride content: reproducibility of 1H MR spectroscopy with respiratory navigator gating in volunteers. , 2007, Radiology.

[15]  Benjamin D. Levine,et al.  Cardiac Steatosis in Diabetes Mellitus: A 1H-Magnetic Resonance Spectroscopy Study , 2007, Circulation.

[16]  P. Raskin,et al.  Effect of Pioglitazone Therapy on Myocardial and Hepatic Steatosis in Insulin-Treated Patients with Type 2 Diabetes , 2007, Journal of Investigative Medicine.

[17]  K. O’Shea,et al.  Potential Impact of Carbohydrate and Fat Intake on Pathological Left Ventricular Hypertrophy , 2022 .

[18]  I. Shiojima,et al.  Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway. , 2006, Genes & development.

[19]  R. Mobini,et al.  Hyperinsulinemia: effect on cardiac mass/function, angiotensin II receptor expression, and insulin signaling pathways. , 2006, American journal of physiology. Heart and circulatory physiology.

[20]  A. Bonen,et al.  Cardiac substrate uptake and metabolism in obesity and type-2 diabetes: Role of sarcolemmal substrate transporters , 2005, Molecular and Cellular Biochemistry.

[21]  J. McGavock,et al.  Determination of triglyceride in the human myocardium by magnetic resonance spectroscopy: reproducibility and sensitivity of the method. , 2005, American journal of physiology. Endocrinology and metabolism.

[22]  S. Nunoda,et al.  Quantitative approach to the histopathology of the biopsied right ventricular myocardium in patients with diabetes mellitus , 1985, Heart and Vessels.

[23]  W. Burmeister,et al.  Die Körperoberfiächenformel nach DuBois und DuBois als Repräsentant der Körperzellmasse bei Männern im Alter zwischen 21 und 51 Jahren , 1966, Klinische Wochenschrift.

[24]  G. Noon,et al.  Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[25]  Thomas H Marwick,et al.  Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications. , 2004, Endocrine reviews.

[26]  B. Rodrigues,et al.  Metabolic disturbances in diabetic cardiomyopathy , 1998, Molecular and Cellular Biochemistry.

[27]  E. Moser,et al.  1H NMR relaxation times of skeletal muscle metabolites at 3 T , 2004, Magnetic Resonance Materials in Physics, Biology and Medicine.

[28]  G. Metzger,et al.  Myocardial triglycerides and systolic function in humans: In vivo evaluation by localized proton spectroscopy and cardiac imaging , 2003, Magnetic resonance in medicine.

[29]  D. Severson,et al.  Age-dependent changes in metabolism, contractile function, and ischemic sensitivity in hearts from db/db mice. , 2003, Diabetes.

[30]  M. Roden,et al.  Effects of insulin treatment in type 2 diabetic patients on intracellular lipid content in liver and skeletal muscle. , 2002, Diabetes.

[31]  J. Ross,et al.  Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[32]  A. Bonen,et al.  Insulin increases FA uptake and esterification but reduces lipid utilization in isolated contracting muscle. , 2001, American journal of physiology. Endocrinology and metabolism.

[33]  M. Fujita,et al.  Abnormal myocardial free fatty acid utilization deteriorates with morphological changes in the hypertensive heart. , 2001, Japanese circulation journal.

[34]  Daniel S. Ory,et al.  Palmitate-induced Apoptosis Can Occur through a Ceramide-independent Pathway* , 2001, The Journal of Biological Chemistry.

[35]  L. Orci,et al.  Lipotoxic heart disease in obese rats: implications for human obesity. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[36]  V A Zammit,et al.  Carnitine acyltransferases: functional significance of subcellular distribution and membrane topology. , 1999, Progress in lipid research.

[37]  T W Redpath,et al.  Determination of normal regional left ventricular function from cine-MR images using a semi-automated edge detection method. , 1999, Magnetic resonance imaging.

[38]  G. Nickenig,et al.  Insulin induces upregulation of vascular AT1 receptor gene expression by posttranscriptional mechanisms. , 1998, Circulation.

[39]  J. Mccormack,et al.  Regulation of energy substrate metabolism in the diabetic heart. , 1997, Cardiovascular research.

[40]  R. DeFronzo PATHOGENESIS OF TYPE 2 DIABETES: METABOLIC AND MOLECULAR IMPLICATIONS FOR IDENTIFYING DIABETES GENES , 1997 .

[41]  C. Kahn,et al.  Cross-talk between the insulin and angiotensin signaling systems. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[42]  B. Kemp,et al.  Insulin activation of acetyl-CoA carboxylase accompanied by inhibition of the 5'-AMP-activated protein kinase. , 1992, The Journal of biological chemistry.

[43]  J C Stanley,et al.  The glucose-fatty acid cycle. Relationship between glucose utilization in muscle, fatty acid oxidation in muscle and lipolysis in adipose tissue. , 1981, British journal of anaesthesia.

[44]  S. Ahmed,et al.  Evidence for cardiomyopathy in familial diabetes mellitus. , 1977, The Journal of clinical investigation.

[45]  W. Burmeister,et al.  [The body surface formula of DuBois and DuBois as a representative of the body cell mass in men between the ages of 21 and 51 years]. , 1966, Klinische Wochenschrift.

[46]  E. Newsholme,et al.  The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. , 1963, Lancet.