Journal of Diabetes & Metabolism

ISSN - 2155-6156


Commentary - (2014) Volume 5, Issue 12

Insulin Resistance, Type 2 Diabetes and Atherosclerosis

Roever L1,2*, Casella-Filho A1, Dourado PMM1, ES Resende2 and Chagas ACP3
1Heart Institute (InCor), HCFMUSP- University of São Paulo Medical School, São Paulo, Brazil
2Federal University of Uberlândia, Brazil
3Faculty of Medicine ABC, Santo André, Brazil
*Corresponding Author: Roever L, Laboratory of Vascular Biology, Heart Institute (InCor), University of São Paulo Medical School, Av. Dr.Enéas De Carvalho Aguiar, 44 05403-900, São Paulo, Brazil, Tel: 55-11 30695259, Fax: 55-11 30695261 Email:


Insulin resistance is a hallmark of type 2 diabetes mellitus and is associated with a metabolic and cardiovascular cluster of disorders (dyslipidaemia, hypertension, obesity, glucose intolerance, metabolic syndrome and endothelial dysfunction), each of which is an independent risk factor for Cardiovascular Disease (CVD). Many prospective studies have documented an association between insulin resistance and accelerated CVD in patients with type 2 diabetes. Insulin resistance and lipotoxicity represent the missing links that help to explain the accelerated rate of CVD in type 2 diabetic patients. Accumulation of toxic lipid metabolites in muscle, liver, adipocytes, beta cells and arterial tissues contributes to insulin resistance, beta cell dysfunction and accelerated atherosclerosis, respectively, in type 2 diabetes. Treatment with diet, exercise and drugs mobilizes fat out of tissues, leading to enhanced insulin sensitivity, improved beta cell function and decreased atherogenesis.

Keywords: Glycemic control; Dyslipidemia; Cardiovascular risk; Epidemiology


Type 2 diabetes mellitus is a complex disorder complicated by microvascular and macrovascular disease [1]. Hyperglycaemia is the major risk factor for microvascular complications and reduction in HbA1c decreases the incidence of complications are a major cause of morbidity, macrovascular complications represent the primary cause of mortality with heart attacs and stroke accounting for around 80% of all deaths [2-5].

Understanding atherosclerosis in diabetes and instituting therapy guided by emerging evidence should improve outcomes in patients. Clinical manifestations of atherosclerosis occur primarily in 3 vascular beds: coronary arteries, lower extremities, and extracranial carotid arteries. Diabetes increases the incidence and accelerates the clinical course of each vascular bed. The evidence supports aggressive antiatherosclerotic management strategies upon diagnosis of type 2 diabetes to minimize the risk of cardiovascular morbidity and mortality [6-9]. Risk factors occur simultaneously,, although such interactions are difficult to quantify (Figure 1).


Figure 1: Risks of cardiovascular (CV) outcomes in diabetes.

This review will explore the current understanding of atherosclerosis and the existing researches supporting the association between insulin resistance, type 2 diabetes and atherosclerosis as well the atherosclerotic complications of diabetes. We focus on type 2 diabetes, characterized by insulin resistance and inadequate beta cell insulin secretion, because these patients represent more than 90% of those with diabetes and atherosclerosis.

Hyperglycaemia and Cardiovascular Disease

The negative results of the ACCORD, ADVANCE and VADT studies, in which intensified glycaemic control failed to reduce vascular complications, it is reasonable to ask which role hyperglycaemia plays in the development of cardiovascular disease (CVD) [9-12]. Epidemiological analysis of the UKPDS demonstrated that the rising of HbA1c was associated with increased risk of myocardial infarction and stroke [3].

The increased hazard ratio was modest and the reduction in HbA1c following insulin or sulfonylurea therapy did not significantly decrease myocardial infarction or stroke, although long-term follow up did demonstrate a significant reduction in atherosclerotic cardiovascular events.

The results of the Hoorn Study, 8 years of follow-up, 185 subjects died; 98 of cardiovascular causes. Fasting plasma glucose was only predictive in the diabetic range, although the risks started to increase at about 6.1 mmol/l. Post-load glucose and HbA1c values were, even within the non-diabetic range, associated with an increased risk (p for linear trend <0.05). These increased risks were mostly, but not completely, attributable to known cardiovascular risk factors [47].

Insulin and Atherosclerosis

Several in vivo and in vitro studies have demonstrated that insulin can promote atherogenesis. Insulin promotes de novo lipogenesis and increases hepatic VLDL synthesis, via the stimulation of sterol regulatory element- binding protein-1c and by the inhibition of acetyl- CoA carboxylase [16-21].

Insulin administration prevented regression of coronary atherosclerosis, when low-cholesterol diet was instituted. Alloxaninduced diabetic rabbits fed with a high-cholesterol diet have developed marked hypercholesterolaemia, but their aorta remained free of atherosclerotic plaques [22]. Finally, insulin therapy is frequently associated with weight gain. Several studies designed to reduce HbA1c <7.0% with large insulin doses failed to achieve the targeted HbA1c goal and resulted in weight gain. This is of major concern since the current diabetes epidemic is being driven by obesity, a major risk factor for CVD [23-26].

Studies in man demonstrated that impaired IRS-1 tyrosine phosphorylation/PI-3 kinase activation in lean type 2 diabetic and obese non-diabetic participants causes a profound defect in glucose transport/phosphorylation and glycogen synthesis. Nitric oxide production is impaired because nitric oxide synthase is activated by the same PI-3 kinase pathway, resulting in endothelial dysfunction and accelerated atherosclerosis. This pathogenic sequence establishes the molecular basis linking insulin resistance, inflammation and accelerated atherosclerosis in patients with type 2 diabetes mellitus and may help to explain the missing 30% CVD risk that cannot be explained by circulating cardiovascular risk factors [27-35].

Diabetes and Vascular Smooth Muscle Function

The impact of diabetes mellitus on vascular function is not limited to the endothelium. In patients with type 2 diabetes mellitus, the vasodilator response to exogenous NO donors is diminished. Moreover, vasoconstrictor responsiveness to exogenous vasoconstrictors, such as endothelin-1, is reduced. Dysregulation of vascular smooth muscle function is exacerbated by impairments in sympathetic nervous system function. Diabetes increases PKC activity, NF-κΒ production, and generation of oxygen-derived free radicals in vascular smooth muscle [36-41].

Epidemiological studies have provided convincing evidence that the risk of CVD is increased by the presence of diabetes and that the increased risk is related to the extent of glycemic control. However, epidemiological studies provide no insight into causality. In vitro studies have provided important clues to the mechanism by which hyperglycemia might lead to atherosclerosis.

Diabetes and atherosclerosis are major causes of disability and death in patients with diabetes mellitus. Diabetes mellitus substantially increases the risk of developing coronary, cerebrovascular, and peripheral arterial disease.


In T2DM, IR increases the mobilization of free fatty acids from adipose tissue. Three mechanisms across which there is increased very low-density lipoproteins hepatic production: an increased lipogenesis, an exacerbation of substrate availability, and decreased apolipoprotein B-100 (ApoB) degradation. The lipid profile marked by low high-density lipoprotein cholesterol (HDL-C), high triglycerides (Tgs), increased ApoB synthesis and small dense LDL particles. This LDL subtype is more inclined to oxidation, playing an important role in atherogenesis. Stronger than LDL cholesterol, a low HDL-C or lonely elevated Tgs, atherogenic dyslipidaemia (Low HDL-C and ApoA, elevation of both fasting and post-prandial Tgs, small dense LDL particles and elevation of ApoB) is in T2DM patients a self-determining predictor of cardiovascular risk. The protective function of HDL may be lost in type 2 diabetics owing to alterations of the protein, resulting in a prooxidant, inflammatory phenotype [42-43]. Association exists between elevation of TGs-rich particles and their remnants, low HDL-C and cardiovascular risk,. Cardiovascular event rates were significantly greater in those with dyslipidaemia: LDL-C >2.6 mmol/L, HDL-C ≤ 0.88 mmol/L and TGs ≥ 2.3 mmol/L, as is proved in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study and in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study [42-47].

IR is commonly observed in the metabolic syndrome, in which multiple metabolic risk factors are co-existed including abdominal obesity, hyperglycemia, hyperinsulinemia, dyslipidemia, hypertension, and hyperhomocysteinemia. Patients with the metabolic syndrome are at increased risk of developing coronary heart disease, stroke and T2DM. Future studies to identify molecular basis of impaired insulin signaling in different tissues would lead to the discovery of novel therapeutic strategies for IR-related metabolism syndrome to reduce the risk of cardiovascular disease.


  1. Defronzo RA (2009) Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 58: 773-795.
  2. Diabetes Control and Complications Trial Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329: 977–986.
  3. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, et al. (2000) Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321: 405-412.
  4. Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H (2001) Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes. Diabetologia 44 Suppl 2: S14-21.
  5. Beckman JA, Creager MA, Libby P (2002) Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 287: 2570-2581.
  6. ResnickHE, Shorr RI, Kuller L, Franse L, Harris TB (2001) Prevalence and clinical implications of American Diabetes Association-defined diabetes and other categories of glucose dysregulation in older adults: the health, aging and body composition study. J ClinEpidemiol 54: 869-876.
  7. Feskens EJ, Kromhout D (1992) Glucose tolerance and the risk of cardiovascular disease: the Zutphen Study. J ClinEpidemiol 45: 1327-1334.
  8. Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M (1998) Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 339: 229-234.
  9. Executive summary of the third report of the National Cholesterol Education Program (NCEP) (2001) .Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 285: 2486-2497.
  10. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, Goff DC Jr, et al. (2008) Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 358: 2545-2559.
  11. Advance Collaborative Group, Patel A, MacMahon S, Chalmers J, Neal B, et al. (2008) Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 358: 2560-2572.
  12. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, et al. (2009) Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 360: 129-139.
  13.  (1998) Intensive blood-glucosecontrol with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352: 837-853.
  14. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA (2008) 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 359: 1577-1589.
  15. Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, et al. (2005) Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 353: 2643-2653.
  16. Kashyap SR, Defronzo RA (2007) The insulin resistance syndrome: physiological considerations. DiabVasc Dis Res 4: 13-19.
  17. DeFronzo RA, Ferrannini E (1991) Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 14: 173-194.
  18. Defronzo RA (2006) Is insulin resistance atherogenic? Possible mechanisms. AtherosclerSuppl 7: 11-15.
  19. Koopmans SJ, Kushwaha RS, DeFronzo RA (1999) Chronic physiologic hyperinsulinemia impairs suppression of plasma free fatty acids and increases de novo lipogenesis in conscious normal rats. Metabolism 48: 330–337.
  20. Tobey TA, Greenfield M, Kraemer F, Reaven GM (1981) Relationship between insulin resistance, insulin secretion, very low density lipoprotein kinetics and plasma triglyceride levels in normotriglyceridemic man. Metabolism 30: 165–171.
  21. Azzout-Marniche D, Bécard D, Guichard C, Foretz M, Ferré P, et al. (2000) Insulin effects on sterol regulatory-element-binding protein-1c (SREBP-1c) transcriptional activity in rat hepatocytes. Biochem J 350 Pt 2: 389-393.
  22. DUFF GL, McMILLAN GC (1949) The effect of alloxan diabetes on experimental cholesterol atherosclerosis in the rabbit. J Exp Med 89: 611-630.
  23. Henry RR, Gumbiner B, Ditzler T, Wallace P, Lyon R, Glauber HS (1993) Intensive conventional insulin therapy for type II diabetes. Metabolic effects during a 6-month outpatient trial. Diabetes Care 16: 21–31.
  24. Holman RR, Thorne KI, Farmer AJ, Davies MJ, Keenan JF, et al. (2007) Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N Engl J Med 357: 1716-1730.
  25. Calle EE, Thun MJ, Petrelli JM, Rodriguez C, Heath CW Jr (1999) Body-mass index and mortality in a prospective cohort of U.S. adults. N Engl J Med 341: 1097-1105.
  26. Allison DB, Fontaine KR, Manson JE, Stevens J, VanItallie TB (1999) Annual deaths attributable to obesity in the United States. JAMA 282: 1530-1538.
  27. Pendergrass M, Bertoldo A, Bonadonna R, Nucci G, Mandarino L, et al. (2007) Muscle glucose transport and phosphorylation in type 2 diabetic, obese nondiabetic, and genetically predisposed individuals. Am J PhysiolEndocrinolMetab 292: E92-100.
  28. Pendergrass M, Koval J, Vogt C, Yki-Jarvinen H, Iozzo P, et al. (1998) Insulin-induced hexokinase II expression is reduced in obesity and NIDDM. Diabetes 47: 387-394.
  29. Kashyap SR, Roman LJ, Lamont J, Masters BS, Bajaj M (2005) Insulin resistance is associated with impaired nitric oxide synthase (NOS) activity in skeletal muscle of type 2 diabetic subjects. J ClinEndocrinolMetab 90: 1100–1105.
  30. Kashyap SR, Lara A, Zhang R, Park YM, DeFronzo RA (2008) Insulin reduces plasma arginase activity in type 2 diabetic patients. Diabetes Care 31: 134-139.
  31. Caballero AE1, Arora S, Saouaf R, Lim SC, Smakowski P, et al. (1999) Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes. Diabetes 48: 1856-1862.
  32. Cersosimo E, DeFronzo RA (2006) Insulin resistance and endothelial dysfunction: the road map to cardiovascular diseases. Diabetes Metab Res Rev 22: 423-436.
  33. Ross R (1993) The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362: 801-809.
  34. Hsueh WA, Lyon CJ, Quiñones MJ (2004) Insulin resistance and the endothelium. Am J Med 117: 109-117.
  35. Behrendt D, Ganz P (2002) Endothelial function. From vascular biology to clinical applications. Am J Cardiol 90: 40L-48L.
  36. Williams SB, Cusco JA, Roddy MA, Johnstone MT, Creager MA (1996) Impaired nitric oxide–mediated vasodilation in patients with non–insulin-dependent diabetes mellitus. J Am CollCardiol 27: 567–574.
  37. Inoguchi T, Li P, Umeda F, Yu HY, Kakimoto M, Imamura M (2000) High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C–dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes 49: 1939–1945.
  38. Cardillo C, Campia U, Bryant MB, Panza JA (2002) Increased activity of endogenous endothelin in patients with type II diabetes mellitus. Circulation 106: 1783-1787.
  39. Nugent AG, McGurk C, Hayes JR, Johnston GD (1996) Impaired vasoconstriction to endothelin 1 in patients with NIDDM. Diabetes 45: 105-107.
  40. McDaid EA, Monaghan B, Parker AI, Hayes JR, Allen JA (1994) Peripheral autonomic impairment in patients newly diagnosed with type II diabetes. Diabetes Care 17: 1422-1427.
  41. Hattori Y, Hattori S, Sato N, Kasai K (2000) High-glucose-induced nuclear factor kappaB activation in vascular smooth muscle cells. Cardiovasc Res 46: 188-197.
  42. Cannon CP (2008) Mixed dyslipidemia, metabolic syndrome, diabetes mellitus, and cardiovascular disease: clinical implications. Am J Cardiol102: 5L-9L.
  43. Sorrentino SA, Besler C, Rohrer L, Meyer M, Heinrich K, (2010) Endothelial- vasoprotective effects of high-density lipoprotein are impaired in patients with type 2 diabetes mellitus but are improved after extended-release niacin therapy. Circulation 121: 110-122.
  44. Chapman MJ, Ginsberg HN, Amarenco P, Andreotti F, Borén J, et al. (2011) Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 32: 1345-1361.
  45. Miller M, Stone NJ, Ballantyne C, Bittner V, Criqui MH, et al. (2011) Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation 123: 2292-333.
  46. Miller M, Stone NJ, Ballantyne C, Bittner V, Criqui MH, et al. (2011) Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation 123: 2292-2333.
  47. de Vegt F, Dekker JM, Ruhé HG, Stehouwer CD, Nijpels G, et al. (1999) Hyperglycaemia is associated with all-cause and cardiovascular mortality in the Hoorn population: the Hoorn Study. Diabetologia 42: 926-931.
Citation: Roever L, Casella-Filho A, Dourado PMM, Resende ES, Chagas ACP (2014) Insulin Resistance, Type 2 Diabetes and Atherosclerosis. J Diabetes Metab 5:464.

Copyright: © 2014 Roever L, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.