Diabetes and Heart Failure: Is it Hyperglycemia or Hyperinsulinemia?

Author(s): Triantafyllos Didangelos*, Konstantinos Kantartzis.

Journal Name: Current Vascular Pharmacology

Volume 18 , Issue 2 , 2020

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Graphical Abstract:


The cardiac effects of exogenously administered insulin for the treatment of diabetes (DM) have recently attracted much attention. In particular, it has been questioned whether insulin is the appropriate treatment for patients with type 2 diabetes mellitus and heart failure. While several old and some new studies suggested that insulin treatment has beneficial effects on the heart, recent observational studies indicate associations of insulin treatment with an increased risk of developing or worsening of pre-existing heart failure and higher mortality rates. However, there is actually little evidence that the associations of insulin administration with any adverse outcomes are causal. On the other hand, insulin clearly causes weight gain and may also cause serious episodes of hypoglycemia. Moreover, excess of insulin (hyperinsulinemia), as often seen with the use of injected insulin, seems to predispose to inflammation, hypertension, dyslipidemia, atherosclerosis, heart failure, and arrhythmias. Nevertheless, it should be stressed that most of the data concerning the effects of insulin on cardiac function derive from in vitro studies with isolated animal hearts. Therefore, the relevance of the findings of such studies for humans should be considered with caution. In the present review, we summarize the existing data about the potential positive and negative effects of insulin on the heart and attempt to answer the question whether any adverse effects of insulin or the consequences of hyperglycemia are more important and may provide a better explanation of the close association of DM with heart failure.

Keywords: Diabetes, insulin, heart failure, diastolic dysfunction, systolic dysfunction, cardiomyopathy, autonomic neuropathy.

Iliadis F, Kadoglou N, Didangelos T. Insulin and the heart. Diabetes Res Clin Pract 2011; 93(Suppl. 1): S86-91.
Karamitsos DT. Antiatheromatic effects of insulin. Diabetes Res Clin Pract 2011; 93(Suppl. 1): S105-8.
Gilbert RE, Krum H. Heart failure in diabetes: Effects of anti-hyperglycaemic drug therapy. Lancet 2015; 385: 2107-17.
Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373: 2117-28.
Smooke S, Horwich TB, Fonarow GC. Insulin-treated diabetes is associated with a marked increase in mortality in patients with advanced heart failure. Am Heart J 2005; 149: 168-74.
Herman ME, O’Keefe JH, Bell DSH, et al. Insulin therapy increases cardiovascular risk in type 2 diabetes. Prog Cardiovasc Dis 2017; 60: 422-34.
Solang L, Malmberg K, Ryden L. Diabetes mellitus and congestive heart failure. Further knowledge needed. Eur Heart J 1999; 20: 789-95.
Bauters C, Lamblin N, Mc Fadden EP, et al. Influence of diabetes mellitus on heart failure risk and outcome. Cardiovasc Diabetol 2003; 2: 1.
McMurray JJ, Gerstein HC, Holman RR, et al. Heart failure: A cardiovascular outcome in diabetes that can no longer be ignored. Lancet Diabetes Endocrinol 2014; 2: 843-51.
Bell DS. Heart failure: The frequent, forgotten and often fatal complication of diabetes. Diabetes Care 2003; 26: 2433-41.
Bertoni AG, Hundley WG, Massing MW, et al. Heart failure prevalence, incidence, and mortality in the elderly with diabetes. Diabetes Care 2004; 27: 699-703.
De Groote P, Lamblin N, Mouquet F, et al. Impact of diabetes mellitus on long-term survival in patients with congestive heart failure. Eur Heart J 2004; 25: 656-62.
Raev DC. Which left ventricular function is impaired earlier in the evolution of diabetic cardiomyopathy? An echocardiographic study of young type I diabetic patients. Diabetes Care 1994; 17: 633-9.
Lind M, Bounias I, Olsson M, et al. Glycaemic control and incidence of heart failure in 20,985 patients with type 1 diabetes: an observational study. Lancet 2011; 378: 140-6.
Iribarren C, Karter AJ, Go AS, et al. Glycemic control and heart failure among adult patients with diabetes. Circulation 2001; 103: 2668-73.
Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: The Framingham study. The Am J Cardiol 1974; 34: 29-34.
Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): Prospective observational study. BMJ 2000; 321: 405-12.
Bahrami H, Bluemke DA, Kronmal R, et al. Novel metabolic risk factors for incident heart failure and their relationship with obesity: The MESA (Multi-Ethnic Study of Atherosclerosis) study. J Am Coll Cardiol 2008; 51: 1775-83.
Liu JE, Palmieri V, Roman MJ, et al. The impact of diabetes on left ventricular filling pattern in normotensive and hypertensive adults: The Strong Heart Study. J Am Coll Cardiol 2001; 37: 1943-9.
van den Berge JC, Constantinescu AA, Boiten HJ, et al. Short- and long-term prognosis of patients with acute heart failure with and without diabetes: Changes over the last three decades. Diabetes Care 2018; 41: 143-9.
Gaede P, Vedel P, Parving HH, et al. Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: The Steno type 2 randomised study. Lancet 1999; 353: 617-22.
Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. The 2003; 348: 383-93.
Gaede P, Lund-Andersen H, Parving HH, et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008; 358: 580-91.
Oellgaard J, Gaede P, Rossing P, et al. Reduced risk of heart failure with intensified multifactorial intervention in individuals with type 2 diabetes and microalbuminuria: 21 years of follow-up in the randomised Steno-2 study. Diabetologia 2018; 61: 1724-33.
Gaede P, Oellgaard J, Carstensen B, et al. Years of life gained by multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: 21 years follow-up on the Steno-2 randomised trial. Diabetologia 2016; 59: 2298-307.
de Jong M, van der Worp HB, van der Graaf Y, et al. Pioglitazone and the secondary prevention of cardiovascular disease. A meta-analysis of randomized-controlled trials. Cardiovasc Diabetol 2017; 16: 134.
Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013; 369: 1317-26.
Erdmann E, Charbonnel B, Wilcox RG, et al. Pioglitazone use and heart failure in patients with type 2 diabetes and preexisting cardiovascular disease: Data from the PRO-active study (PROactive 08). Diabetes Care 2007; 30: 2773-8.
Packer M. worsening heart failure during the use of DPP-4 Inhibitors: Pathophysiological mechanisms, clinical risks, and potential influence of concomitant antidiabetic medications. JACC Heart Fail 2018; 6: 445-51.
Zelniker TA, Wiviott SD, Raz I, et al. Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose co-transporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus: A systematic review and meta-analysis of cardiovascular outcomes trials. Circulartion 2019; 139(17): 2022-31.
Abdul-Ghani M, Del Prato S, Chilton R, et al. SGLT2 Inhibitors and cardiovascular risk: Lessons learned From the EMPA-REG OUTCOME study. Diabetes Care 2016; 39: 717-25.
Heerspink HJ, Perkins BA, Fitchett DH, et al. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: Cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation 2016; 134: 752-72.
Tanaka A, Node K. Emerging roles of sodium-glucose cotransporter 2 inhibitors in cardiology. J Cardiol 2017; 69: 501-7.
Poulsen MK, Henriksen JE, Dahl J, et al. Left ventricular diastolic function in type 2 diabetes mellitus: Prevalence and association with myocardial and vascular disease. Circ Cardiovasc Imaging 2010; 3: 24-31.
Dargie HJ, Hildebrandt PR, Riegger GA, et al. A randomized, placebo-controlled trial assessing the effects of rosiglitazone on echocardiographic function and cardiac status in type 2 diabetic patients with New York Heart Association Functional Class I or II Heart Failure. J Am Coll Cardiol 2007; 49: 1696-704.
Giles TD, Elkayam U, Bhattacharya M, et al. Comparison of pioglitazone vs. glyburide in early heart failure: Insights from a randomized controlled study of patients with type 2 diabetes and mild cardiac disease. Congest Heart Fail 2010; 16: 111-7.
Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017; 377: 644-57.
Didangelos TP, Arsos G, Karamitsos T, et al. Left ventricular systolic and diastolic function in normotensive type 2 diabetic patients with or without autonomic neuropathy: A radionuclide ventriculography study. Angiology 2014; 65: 877-82.
Russo I, Frangogiannis NG. Diabetes-associated cardiac fibrosis: Cellular effectors, molecular mechanisms and therapeutic opportunities. J Mol Cell Cardiol 2016; 90: 84-93.
Boudina S, Abel ED. Mitochondrial uncoupling: A key contributor to reduced cardiac efficiency in diabetes. Physiology (Bethesda) 2006; 21: 250-8.
Boudina S, Sena S, Theobald H, et al. Mitochondrial energetics in the heart in obesity-related diabetes: Direct evidence for increased uncoupled respiration and activation of uncoupling proteins. Diabetes 2007; 56: 2457-66.
How OJ, Aasum E, Severson DL, et al. Increased myocardial oxygen consumption reduces cardiac efficiency in diabetic mice. Diabetes 2006; 55: 466-73.
Goldberg IJ. 2017 George lyman duff memorial lecture: Fat in the blood, fat in the artery, fat in the heart: Triglyceride in physiology and disease. Arterioscler Thromb Vasc Biol 2018; 38: 700-6.
Laakso M. Heart in diabetes: A microvascular disease. Diabetes Care 2011; 34(Suppl. 2): S145-9.
Jia G, Hill MA, Sowers JR. Diabetic cardiomyopathy: An update of mechanisms contributing to this clinical entity. Circ Res 2018; 122: 624-38.
Vinik AI, Ziegler D. Diabetic cardiovascular autonomic neuropathy. Circulation 2007; 115: 387-97.
Fukuda K, Kanazawa H, Aizawa Y, et al. Cardiac innervation and sudden cardiac death. Circ Res 2015; 116: 2005-19.
Rennings AJ, Smits P, Stewart MW, et al. Autonomic neuropathy predisposes to rosiglitazone-induced vascular leakage in insulin-treated patients with type 2 diabetes: A randomised, controlled trial on thiazolidinedione-induced vascular leakage. Diabetologia 2010; 53: 1856-66.
Pfeifer MA, Weinberg CR, Cook DL, et al. Autonomic neural dysfunction in recently diagnosed diabetic subjects. Diabetes Care 1984; 7: 447-53.
Chaudhary AK, Aneja GK, Shukla S, et al. Study on diastolic dysfunction in newly diagnosed type 2 diabetes mellitus and its correlation with glycosylated haemoglobin (HbA1C). J Clin Diagn Res 2015; 9: 20-2.
Nakai H, Takeuchi M, Nishikage T, et al. Subclinical left ventricular dysfunction in asymptomatic diabetic patients assessed by two-dimensional speckle tracking echocardiography: Correlation with diabetic duration. Eur J Echocardiogr 2009; 10: 926-32.
Ernande L, Bergerot C, Rietzschel ER, et al. Diastolic dysfunction in patients with type 2 diabetes mellitus: Is it really the first marker of diabetic cardiomyopathy? J Am Soc Echocardiogr 2011; 24: 1268-75.e1.
Bhatia RS, Tu JV, Lee DS, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 2006; 355: 260-9.
Boudina S, Abel ED. Diabetic cardiomyopathy revisited. Circulation 2007; 115: 3213-23.
Lautamaki R, Airaksinen KE, Seppanen M, et al. Insulin improves myocardial blood flow in patients with type 2 diabetes and coronary artery disease. Diabetes 2006; 55: 511-6.
Su H, Sun X, Ma H, et al. Acute hyperglycemia exacerbates myocardial ischemia/reperfusion injury and blunts cardioprotective effect of GIK. Am J Physiol Endocrinol Metab 2007; 293: E629-35.
Bertrand L, Horman S, Beauloye C, et al. Insulin signalling in the heart. Cardiovasc Res 2008; 79: 238-48.
Manhiani MM, Duggan AD, Wilson H, et al. Chronic intrarenal insulin replacement reverses diabetes mellitus-induced natriuresis and diuresis. Hypertension 2012; 59: 421-30.
Irsik DL, Chen JK, Brands MW. Chronic renal artery insulin infusion increases mean arterial pressure in male Sprague-Dawley rats. Am J Physiol Renal Physiol 2018; 314: 81-8.
Brands MW, Manhiani MM. Sodium-retaining effect of insulin in diabetes. Am J Physiol Regul Integr Comp Physiol 2012; 303: R1101-9.
Hall JE, Brands MW, Kivlighn SD, et al. Chronic hyperinsulinemia and blood pressure. Interaction with catecholamines? Hypertension 1990; 15: 519-27.
Hall JE, Coleman TG, Mizelle HL, et al. Chronic hyperinsulinemia and blood pressure regulation. Am J Physiol 1990; 258: F722-31.
Pontiroli AE, Alberetto M, Pozza G. Patients with insulinoma show insulin resistance in the absence of arterial hypertension. Diabetologia 1992; 35: 294-5.
Khunti K, Damci T, Meneghini L, et al. Study of Once Daily Levemir (SOLVE): Insights into the timing of insulin initiation in people with poorly controlled type 2 diabetes in routine clinical practice. Diabetes Obes Metab 2012; 14: 654-61.
Gerstein HC, Bosch J, Dagenais GR, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 2012; 367: 319-28.
Nielsen R, Wiggers H, Thomsen HH, et al. Effect of tighter glycemic control on cardiac function, exercise capacity, and muscle strength in heart failure patients with type 2 diabetes: A randomized study. BMJ Open Diabetes Res Care 2016; 4: e000202

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Year: 2020
Page: [148 - 157]
Pages: 10
DOI: 10.2174/1570161117666190408164326
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