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Diabetes/Insulin Resistance


Fasting blood glucose is a strong predictor of risk for diabetes and is one of the traditional diagnostic criteria for prediabetes and T2DM.2 Although the body’s main source of energy is in the form of blood glucose, prolonged exposure to hyperglycemia can lead to insulin resistance, pancreatic β-cell dysfunction, and ultimately diabetes and other complications. Hyperglycemia leads to glycosylated proteins which can promote endothelial dysfunction, vascular permeability, and oxidative stress, which favors the atherogenic modification of LDL particles and increases risk for CAD.1,3 Regular glucose testing will aid in the prevention or management of diabetes and reduce the risk of long-term complications.

  1. Tenenbaum A, et al. Cardiovasc Diabetol 2014;13:159.
  2. American Diabetes Association. Diabetes Care 2015;38(Suppl. 1):S8–S16.
  3. Aronson D, Rayfield EJ. Cardiovasc Diabetol 2002;1:1.


Fasting hemoglobin A1c (HbA1c) level is a strong predictor of risk for diabetes and one of the traditional diagnostic criteria for prediabetes and T2DM. 1 It is formed by the slow, nonenzymatic attachment of glucose to hemoglobin. HbA1c reveals the percentage of red blood cells with glucose attached and provides a measure of glycemic control over a 2- to 3-month period (the lifespan of a red blood cell). HbA1c is useful for monitoring adequacy of glycemic management and risk for developing microvascular complications in patients with diabetes and prediabetes for adequacy of glycemic management and risk for developing microvascular complications.2 Chronic hyperglycemia reflected by HbA1c elevation has been associated with premature aging and increased morbidity and mortality from age-related diseases such as CVD.3

1. American Diabetes Association. Diabetes Care 2015;38(Suppl. 1):S8–S16.                                                            2. Benhalima et al. J Diabetes Complications 2011;25(3):202–207.                                                                                    3. Preuss HG. J Am Coll Nutr 1997;16(5):397–403.


Insulin is a peptide hormone secreted by the β cells of the pancreas in response to glucose elevations in the blood. It regulates circulating glucose levels by inducing glucose uptake in peripheral tissues and inhibiting hepatic glucose production. Elevated insulin levels are an indication of insulin resistance and risk for T2DM and may be related to acceleration of cognitive decline during aging, even in individuals without diabetes.2 The high insulin levels typically seen in insulin-resistant individuals have also been associated with reduced bone strength, which could contribute to increased fracture risk and frailty later in life.3 Insulin measurement is useful in the evaluation and management of women with polycystic ovary syndrome (PCOS), who may manifest insulin resistance associated with androgen excess and features of metabolic syndrome.4 Prospective studies have shown that the highest insulin tertile of a nondiabetic population developed significantly more CVD.1 The combination of elevated serum insulin and elevated apoB indicates very high risk.5

  1. Salazar MR, et al. Diab Vasc Dis Res 2016;13(2):157–163.
  2. Verdile G, et al. Mediators Inflamm 2015;2015:105828.
  3. Srikanthan P, et al. J Bone Miner Res 2014;29(4):796-803.
  4. Jayasena CN, Franks S. Nat Rev Endocrinol 2014;10(10):624–636.
  5. Lamarche B, et al. J Am Med Assoc 1998;279(24):1955–1961.


The fructosamine assay measures the sum of glycated serum proteins (including hemoglobin and albumin), and provides an indication of glycemic control over a 2- to 3-week period, complementing other measures of immediate (glucose) and long-term (HbA1c) glycemic control. High fructosamine levels are linked to microvascular diabetic complications, such as kidney disease or retinopathy, independently of HbA1c.1 As fructosamine responds more quickly than HbA1c to changes in glucose levels, it useful when assessing response to treatment in the short-term and also for clinical conditions that exclude the use of HbA1c, e.g., hemoglobinopathies. Fructosamine was recently demonstrated to strongly predict cardiovascular events and death from any cause in two large population-based cohorts, even after adjustment for glucose and other cardiovascular risk factors.2,3 On the other hand, as has been observed for HbA1c, the associations tended to be J-shaped, with an elevation of risk at the lowest levels of fructosamine, perhaps in part due to chronic inflammation.4

  1. Selvin E, et al. Lancet Diabetes Endocrinol 2014;2(4): 279e88.
  2. Selvin E, et al. Circulation 2015;132(4):269e77
  3. Malmstrom H, et al. Nutr Metab Cardiovasc Dis 2015;25(10):943–950.
  4. Malmstrom H, et al. Nutr Metab Cardiovasc Dis 2016 Sep 2 [Epub ahead of print] doi: 10.1016/j.numecd.2016.08.006


The Homeostasis Model Assessment of Insulin Resistance index (HOMA-IR), uses fasting glucose and insulin measures to estimate whole body insulin resistance by modeling the balance between hepatic glucose output, insulin secretion, and glucose uptake in peripheral tissue [HOMA-IR = fasting insulin (μIU/ml) × fasting glucose (mg/dl)/405].1 HOMA-IR generally increases with insulin resistance and is useful for tracking changes in insulin sensitivity and pancreatic β-cell function over time. It is a better predictor of risk for diabetes and CVD than fasting glucose or fasting insulin measured alone.

  1. Matthews DR, et al. Diabetologia 1985;28:412–419.


C-peptide is a protein fragment produced in the pancreatic β cells when proinsulin is cleaved to form insulin. The circulating concentration of C-peptide is a metric of insulin secretion as it is not as affected as insulin is by pharmacokinetic issues (i.e., C-peptide is not cleared as quickly by the liver). Elevated C-peptide levels are an early indicator of β-cell dysfunction and insulin resistance, and are associated with increased risk of CVD and death.1 C-peptide may help in assessing residual β-cell function and hypoglycemia in patients with diabetes, and in differentiating type 1 from type 2 diabetes.2

  1. Pikkemaat M, et al. Diabet Med 2015;32:85–89.
  2. Owen KR. Diabet Med 2013;30(3):260–266.


Adiponectin is an anti-inflammatory adipokine produced by adipose tissue that protects endothelial function, inhibits atherogenesis, and enhances insulin sensitivity. Low levels of adiponectin may contribute to T2DM and precede other markers of insulin resistance. Although the cardioprotective effects of adiponectin are well established, high levels of adiponectin are paradoxically associated with increased mortality risk, especially in elderly individuals and those with known CVD. This suggests that adiponectin elevation may be a compensatory response to existing disease. Lifestyle modification, visceral fat reduction, and certain medications can increase serum adiponectin levels and improve insulin sensitivity, thus helping to prevent both T2DM and CVD.

  1. Fasshauer M, Bluher M. Trends Pharmacol Sci 2015;36(7):461–470.
  2. Lee, ES et al. Int J Epidemiol 2013;42:1029–1039.


Body fat is an important determinant of sensitivity to insulin, which is also influenced by low-grade inflammatory status. Leptin is another fat-secreted hormone (adipokine) that normally feeds back on the hypothalamus to suppress appetite and enhance energy expenditure.1 Leptin is also plays important roles in regulating glucose and lipid homeostasis, immune function, and bone physiology. As adipose tissue is the main source of circulating leptin, levels are often elevated in overweight/obese individuals. Chronic elevations can lead to hypothalamic leptin resistance whereby the brain does not properly relay the signal to decrease food intake or increase energy expenditure. Higher-than-expected levels of leptin (relative to BMI) may help identify individuals at risk for developing diabetes who are more likely to struggle with weight loss and exercise, and require the most intensive support and care management to achieve lifestyle changes.2 Leptin resistance is thought to promote the development of age-related cognitive decline and neurodegenerative disorders such as Alzheimer disease.3 Low levels of leptin may be associated with lipodystrophy syndromes, prolonged fasting or anorexia nervosa, and congenital leptin deficiency. If indicated, leptin replacement therapies are available.1

  1. Park H, Ahima RS. Metab Clin Exp 2015;64:24–34.
  2. Santoro A, et al. Life Sci 2015;140:64–74.
  3. Procaccini C, et al. Metab Clin Exp 2016;65:1376–1390.


Insulin-like growth factor 1 (IGF-1) is an anabolic hormone produced primarily in the liver and released upon stimulation by growth hormone (GH). IGF-1 plays an active role in the maintenance of muscle mass and strength, in preventing apoptosis, and in protection against oxidative stress. 1 IGF-1 is also a sensitive nutritional marker and is negatively influenced by poor mineral and nutritional status, and proinflammatory cytokines. Low circulating IGF-1 levels are strongly related to sarcopenia, poor muscle strength, and physical performance, especially in the presence of subclinical inflammation.1 Low IGF-1 coupled with high IL-6 confers especially increased risk of functional impairment. Specific minerals such as magnesium, selenium, and zinc, along with adequate protein and energy intake, are important for sustaining IGF-1 levels, which are low at birth (<100 ng/mL), rise steeply during childhood and adolescence, but generally start to decline by the mid-twenties.2 IGF-1 may be considered the crossroad of nutritional, hormonal (affecting other anabolic hormones such as DHEA-S and testosterone), and inflammatory pathways to frailty.1 In young children, IGF-1 deficiency results in growth failure that can be dramatically relieved if GH is given before puberty. In adults, deficiency of GH or IGF-1 may fuel the aging process, and be associated with metabolic syndrome, osteoporosis, and increased risk of cardiovascular events.3 Mineral supplementation may be prudent in those with low serum IGF-1, particularly the elderly or those with a decreased physiological reserve, suboptimal nutritional status, and increased vulnerability to stressors, who may be at risk of developing mobility limitation.

Although the absence of GH and IGF-1 may contribute to aging, increased IGF-1 above physiological levels is considered a risk factor in age-related pathologies such as lung, breast, and prostate cancer.4,5 Intermittent fasting (protein/caloric restriction) under appropriate clinical guidance may lower risk in young to middle-aged adults by reducing circulating IGF-1 to physiological levels. 6 IGF-1 may not be as sensitive a marker for adult onset GH deficiency, a diagnosis which must be evaluated through additional provocative testing such as the insulin tolerance test or the growth hormone-releasing hormone (GHRH)-arginine test.7,8

  1. Maggio M, et al. Nutrients 2013;5:4184-4205.
  2. Le Roith D. N Engl J Med 1997;336 (9):633–640.
  3. Tzanela M. Expert Opin Pharmacother 2007;8(6):787–795.

Free Fatty Acids

Free fatty acids (FFA) that are not esterified to form TG are released from body fat as a source of energy, under the control of insulin and catecholamines. Plasma FFA levels are dynamically regulated by a number of factors including release from adipose tissue, lipolysis of lipoprotein-associated triglycerides, and recent dietary fat intake. Bound to albumin after release, FFA are the major form in which lipids are transported from the fat tissue to sites around the body for utilization. Secretion of insulin after a meal normally suppresses lipolysis, causing a rapid drop in serum FFA.

High circulating FFA levels can impair the body’s response to insulin and cause blood glucose levels to rise by modulating the cascade linking insulin receptors with glucose transporters.1 Increased delivery of FFA to the liver also stimulates increased production of VLDL and TG with enhanced clearance of HDL, promoting an atherogenic lipid profile. Individuals with high FFA levels may therefore be at increased risk of developing insulin resistance, metabolic syndrome, type 2 diabetes, and CVD.2 Clinical studies have shown that high FFA levels are associated with endothelial dysfunction, high blood pressure, atrial fibrillation, and stroke.3,4

  1. Rachek LI, et al. Prog Mol Biol Transl Sci 2014;121:267–292.
  2. Frohnert BI, et al. Diabetes 2013;62:3163–3169.
  3. Sarafidis PA, Bakris GL. J Hum Hypertens 2007;21:12–19.
  4. Choi J-Y, et al. Ann Neurol 2016;79:317–325.


Proinsulin, the precursor to insulin, is synthesized in the pancreatic β cells and is the major storage form of insulin. Cleaved enzymatically into insulin and a fragment called C-peptide in the pancreatic β cells, proinsulin normally enters the circulation in very small quantities, but serum levels rise with age and are significantly elevated in prediabetic states associated with impaired insulin secretion. Serum proinsulin is a highly sensitive indicator of β-cell dysfunction and insulin resistance, and may be one of the earliest warning signs of damage to the β cells.1 High proinsulin levels have been observed in individuals with impaired glucose tolerance, and are a positive risk factor for the development of T2DM.2 In patients with prediabetes and diabetes, elevated proinsulin concentrations provide a stronger prediction of incident CHD than does insulin.3,4 Hyperproinsulinemia may also be seen in patients with pancreatic tumors, chronic renal failure, cirrhosis of the liver, or hyperthyroidism. Clinical interpretation of elevated proinsulin should be made with consideration of insulin (and C-peptide) levels.

  1. Pfutzner A, Forst T. J Diabetes Sci Technol 2011;5(3):784–793.
  2. Pfützner A. J Diabetes Sci Technol 2015;9(6):1307–1312.
  3. Yudkin JS, et al. Diabetologica 2002;45:327–336.
  4. Yudkin JS. Circulation 2002;106(24):e202.

Proinsulin/C-Peptide Ratio

This ratio is a quantitative index of the efficiency with which pancreatic β cells process proinsulin to insulin and C-peptide in the secretory granules.1 When under strain, often resulting from chronic hyperglycemic and insulin resistance states, the β cells may lose their processing capacity and levels of proinsulin in the circulation will rise disproportionately in relation to insulin and C-peptide. The proinsulin/C-peptide ratio is a strong predictor of incident T2DM and provides an early indicator of β-cell injury that precedes the loss of β-cell mass that develops over time.2,3

  1. Loopstra-Masters RC, et al. Diabetologica 2011;54:3047–3054.
  2. Beer SF, et al. Clin Endocrinol (Oxf) 1989;30:379–383.
  3. Bristow AF, Das RE.. J Biol Stand 1988;16(3):179–186.

Anti-GAD Antibody

Glutamic acid decarboxylase (GAD) is an enzyme that catalyzes the synthesis of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter, in GABAergic neurons of the pancreatic islet cells. The anti- anti-GAD IgG test detects GAD65 autoantibodies in the blood, the presence of which indicates autoimmune targeting of β cells and can block the conversion of glutamate to GABA, leading to motor and cognitive problems. Very high levels of GAD antibodies in patients with muscular stiffness, painful spasms, and gait abnormalities are strongly suggestive of neurological disorders including the rare (but underdiagnosed) stiff person syndrome, cerebellar ataxia, and epilepsy.1,2

In the general population, positive (usually lower) levels of anti-GAD antibodies are a highly sensitive, specific marker of type 1 diabetes mellitus (T1DM) and for future onset of diabetes in otherwise healthy individuals, years before clinical symptoms (e.g., hyperglycemia) occur.3 Pancreatic β-cell autoimmunity may also be a feature of diabetes occurring at a later age; up to 10% of patients with T2DM are also positive for at least one islet cell autoantibody, and some will exhibit a form of T1DM with a unique, slow-progressing presentation, referred to as latent autoimmune diabetes of adults (LADA).4-6 LADA patients tend to require insulin treatment earlier than do classic T2DM patients, owing to autoimmune attack on their β cells and very low reserves of C-peptide. Other potential causes of anti-GAD positivity include nonspecific association with other autoimmune disorders (e.g., thyroiditis) or age-related degenerative processes.

  1. Dayalu P, Teener JW.. Semin Neurol 2012;32:544–549.
  2. Tohid H. Neurosciences 2016;21(3):215–222.
  3. Orban T, et al. Diabetes Care 2009;32(12):2269–2274.
  4. Lundgren VM, et al.  Diabetes 2010;59(2):416–422.
  5. Mahadeb YP, et al. Acta Diabetol 2014;51:103–111.
  6. Hawa MI, et al. Diabetes Care 2013;36:908–913.

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