When using complex insulin regimen in old people with diabetes, attention should be paid for the risk of hypoglycemia. In this paper we aim to review and discuss the best glycemic targets as well as the best treatment choices for older people with type 2 diabetes based on current international guidelines.

Life expectancy is defined as the average number of years that a newborn is expected to live assuming that current mortality rates remain the same throughout its life. Global average life expectancy has increased by 5. Latest estimates of life expectancy at birth were of The progressive decline of age-standardized rates of death from non-communicable chronic diseases NCDs, cardiovascular and respiratory diseases, cancer, and diabetes registered globally between and 4 , together with the rising number of people older than 65 years, especially in westernized countries, has led to an increased prevalence of NCDs among elderly, resulting in more years of life spent with morbidity and disability 5.

Diabetes is recognized as an important cause of premature death and disability. Therefore, diabetes is one of the most widespread health burning problems in the elderly, which represent a heterogeneous and complex population as it include both newly diagnosed older diabetic patients and patients with long-standing diabetes with onset in middle or early age 7.

Consequently, management of diabetes in elderly subjects is particularly complex and challenging for clinicians, due to difficulty in individualizing glycemic targets, treatment strategies, coexisting comorbidities, polypharmacy, and hypoglycemic risk.

The aim of this review is to discuss the best glycemic targets as well as the best treatment choices for old people with type 2 diabetes based on current shared international guidelines.

Type 2 diabetes represents the most common metabolic disease in older adults. According to the latest estimates of the International Diabetes Federation IDF , diabetes shows a high prevalence in people older than 65 years 8.

In , the number of diabetic people aged 65—99 was estimated to be China, United States of America and India are the countries with highest numbers of people older than 65 with diabetes.

Similar prevalence rates of diabetes were found in the European Region, reaching values ranging between The main reasons imputable to this spreading may be found in the longer life expectancy, the global diffusion of both unhealthy lifestyle habits and environmental pollution 9.

Moreover, elderly diabetic patients are exposed to a higher risk of cardiovascular complications, including peripheral vascular disease, heart disease, and stroke 10 , and many geriatric syndromes from cognitive impairment to urinary incontinence Several factors participate in the pathophysiology of diabetes in older age.

Chronological age per sè represents a risk factor for many chronic diseases Advanced age leads to the exacerbation of systemic chronic inflammation, oxidative stress, DNA damage, decline of mitochondrial function, cellular senescence, and tissue dysfunction, all conditions which contribute to generate metabolic disorders Indeed, aging is associated with raised levels of pro-inflammatory molecules, including interleukin IL 1, IL-6, IL-8, IL, IL, C-reactive protein, interferons α and β, transforming growth factor β TGF-β , tumor necrosis factor α TNF-α , and serum amyloid Furthermore, the age-related variation of body composition leads to an increase in fat mass, especially visceral adiposity, and an equal decrease in lean and skeletal mass With aging, there is a decline in preadipocyte replication and an expansion of senescent cells in adipose tissue which enhance lipotoxicity and favor the generation of a pro-inflammatory status Moreover, some studies have showed that aging 1 impairs insulin secretion from β-cells in response to endogenous incretins GIP , 2 is associated with reduced insulin sensitivity, and 3 promotes β-cell death by inducing mitochondrial dysfunction In older subjects, abnormalities in both insulin sensitivity and insulin secretion lead gradually to impaired glucose tolerance and consequently to clinically manifest diabetes.

Postprandial hyperglycemia is a characteristic feature of type 2 diabetes in older patients. Therefore, an oral glucose tolerance test should be performed in older subjects with impaired fasting glucose to early detect diabetes, which otherwise could be undiagnosed using fasting plasma glucose alone 7.

Diabetes onset in elderly usually manifest with vague and not specific symptoms, such as dehydration, dry mouth, confusion, fatigue, lethargy, weight loss, and an increased tendency toward genitourinary infections Most common type 2 diabetes comorbidities, including cognitive impairment, disability, depression, apathy, urinary incontinence, polypharmacy, hearing, and visual impairment, falls and fractures, fall under geriatric syndromes 19 Figure 1.

With advanced age, malnutrition, physical inactivity, and unwanted weight loss become more frequent. Therefore, a comprehensive geriatric assessment including screening for microvascular complications, cardiovascular risk factors, and geriatric syndromes should be performed at initial diagnosis of diabetes in elderly patients There is evidence that type 2 diabetes is associated with cognitive dysfunctions.

Older diabetic patients have higher risk to develop mild cognitive impairment MCI , all-cause dementia and Alzheimer's disease Specific mechanisms underlying this association are still unclear; however, main factors involved are vascular dysfunction, high blood pressure, hyperglycemia, hypoglycemic events, insulin resistance, and neuroinflammation Furthermore, depressive and apathic symptoms frequently co-exist with diabetes 23 , and some studies have found that combination of diabetes and depression may express a toxic effect on the brain, increasing the risk for dementia In light of this, the American Diabetes Association ADA recommends for subjects over 65 years old with a level of evidence B a neuro-psychological screening at the initial visit and annually to early detect mild cognitive impairment and depression, by using some specific test Mini-Mental State Examination, Montreal Cognitive Assessment and Geriatric Depression Scale , and minimizing hypoglycemic events to reduce the risk of MCI Type 2 diabetes in elderly is a powerful risk factor for functional limitations, frailty, loss of independence, and disability Moreover, there is evidence that type 2 diabetes increases the risk of fracture risk and secondary hypogonadism, which also contribute to enhance risk of osteoporosis and muscle weakness in men 27 , With aging there is a progressive loss of strength and toughness of skeletal and muscle mass which leads to a status of osteo- and sarcopenia.

Changes in skeletal muscle protein turnover could accelerate these alterations in type 2 diabetic patients 29 , resulting in a greater risk of falling and bone fractures As testosterone decline with advancing age, the assessment of its concentrations may be useful in case of signs and symptoms of overt hypogonadism to better evaluate the risk of fracture in this selected population 31 , Indeed, there is evidence that older patients with type 2 diabetes have an increased risk of hip fractures, particularly in insulin-treated patients, and non-skeletal fall injuries A moderate but regular physical activity and a high adherence to Mediterranean dietary pattern showed some benefits in reducing the risk of falls and physical impairments in patients older than 75 years 34 , The American Geriatrics Society suggests to interrogate older patients about falls at least every 12 months, examine potentially reversible causes of falls medications, environmental factors, limiting factors and perform a complete basic evaluation when an injurious fall occurs level of evidence III, strength B Urinary incontinence is a frequent comorbidity of diabetes, although it is usually not-reported by patients Therefore, according to the American Geriatrics Society, physicians should always perform an annual screening for urinary incontinence which may be an important cause of social isolation, depression, falls, and fractures level of evidence III, strength A Both overtreatment and polypharmacy are very common among frail older diabetic subjects.

The prevalence of polypharmacy regimen, defined as the use of more than 5 medications, increases with age. Furthermore, one-quarter of US older diabetic adults are on potential overtreatment for tight glycemic control using glucose-lowering medications at high risk of hypoglycemia Polypharmacy in older diabetic patients may produce detrimental effects mainly due to increased risk of drug-drug interactions and adverse side effects However, a deintensification rather than intensification of pharmacological therapy should be advisable in diabetic patients in older age, in consideration of both benefits and risks associated with complex therapeutic regimens.

Moreover, older adults with diabetes should annually update the list of used medications for their own clinicians level of evidence II, strength A Older patients represent a very heterogeneous and challenging population concerning diabetes care and treatment. While treating diabetes in elderly, clinicians should be always aware of maintaining a good quality of life.

Patient-centered glycemic targets are needed in order to achieve the glycemic control avoiding dangerous or extreme glucose excursions. Elderly patients are highly vulnerable to hypoglycemic events, as a consequence of progressive age-related decrease in β-adrenergic receptor function.

Indeed, hypoglycemia in older age has been associated with an increased risk to develop cognitive impairment, dementia, all-cause hospitalization, and all cause mortality 42 — Use of insulin or insulin secretagogues, polypharmacy, coexisting comorbidities, renal insufficiency, dehydration, impairment of counter-regulatory responses represent the main predisposing risk factors for hypoglycemic episodes Assessment of potential risk factors for hypoglycemia is an important part of the clinical management of older diabetic subjects.

Moreover, both patients and caregivers have to be trained and well-educated on the prevention, detection, and treatment of hypoglycemic events On the other hand, both untreated or undertreated hyperglycemic events should be avoided in old people, given the higher risk of dehydration, dizziness, falls, and long-term mortality The paucity of randomized controlled trials RCTs for diabetes treatment in older adults does not allow to clearly establish the most appropriate therapeutic goals in the elderly.

standard therapy, vs. Actually, the best glycemic target to achieve for elderly diabetic patients is still a matter of debate Table 1 summarizes the glycemic goals for elderly affected by diabetes according different international guidelines. These therapeutic objectives are in line with those for adults older than 65 years indicated by American Geriatrics Society HbA1c ranging between 7.

Beyond tailored glycemic goals, ADA highlights the importance of controlling any other cardiovascular risk factor with an appropriate lipid-lowering, anti-platelet, and anti-hypertensive therapy.

Table 1. Glycemic targets in elderly patients according to the current international guidelines. Differing from ADA, the American Association of Clinical Endocrinologists AACE advises an HbA1c goal of 6. Studies comparing the effectiveness of anti-diabetes drugs in elderly are lacking, due to the exclusion of older diabetic adults from RCTs, given the high number of comorbidity and their enhanced cardiovascular risk.

Every therapeutic strategy should be chosen considering age, health status, self-manageability, cognitive and nutritional status, and comorbidities Table 2. Generally, in older adults at higher risk to experience hypoglycemic events, medications with low risk of hypoglycemia should be preferred.

Furthermore, it is advisable to simplify poly-pharmacological regimens in order to reduce adverse effects and achieve most appropriate glycemic goals. The latest consensus on the management of hyperglycemia in type 2 diabetes of the ADA and the European Association for the Study of Diabetes EASD 57 recommends to use drugs with proven cardiovascular benefit in patients with established clinical cardiovascular disease.

Anti-hyperglycemic agents considered safe and effective for type 2 diabetic older patients can be divided in oral and injectable drugs Table 3. Table 2. Most frequent clinical phenotypes in elderly with suggested HbA1c target and glucose-lowering treatment.

Table 3. Glucose-lowering medications available in Europe with specific characteristics to drive the treatment choice for old people with type 2 diabetes. Metformin is the first-line medication recommended in the management of type 2 diabetes.

It reduces both insulin-resistance and hepatic gluconeogenesis, lowering glucose concentrations without increasing hypoglycemic risk. Moreover, a once daily extended-release formulation of metformin is now available, which is associated with a better gastrointestinal tolerability profile and patients' compliance.

As it is excreted by the urine, a good glomerular filtration rate is needed The main adverse effects described are commonly gastrointestinal symptoms and very rarely lactic acidosis. It is a safe and effective anti-hyperglycemic drug, with low cost, and minimal risk of hypoglycemia.

Nevertheless, it should be carefully used under conditions of congestive heart failure and hepatic dysfunction, which could increase the risk of lactic acidosis Thiazolidinediones also act as insulin sensing agent influencing transcriptional processes by activation of peroxisome proliferator-activated receptor-γ PPAR-γ.

Pioglitazone is the only one remaining drug of this class, as it has proven to be safe in the presence of cardiovascular disease It is characterized by good efficacy, low cost, and no risk of hypoglycemia when used in monotherapy. It can be used even in case of low GFR value 61 starting from the lowest dose of 15 mg to the maximum dose of 45 mg with meals.

Pioglitazone is associated with weight gain and fluid retention, so that it is contraindicated in case of congestive heart failure NYHA class III, IV. Furthermore, it is not advisable to use the drug in older person at risk for falls because it has proven to increase risk of non-osteoporotic bone fractures Finally, it is contraindicated in patients with or at high risk for bladder cancer Sulfonylureas are an insulin secretagogue class, which act by favoring β-cells membrane depolarization and consequently insulin secretion.

They are characterized by high glucose lowering efficacy and low cost, but they should be used with extreme caution because of the high risk of hypoglycemia and weigh gain. Short acting ones with lowest hypoglycemic risk, such as gliclazide, should be preferred in older diabetic patients, when initial therapy with metformin is contraindicated or not tolerated By contrast, long acting sulfonylureas, as glibenclamide, are considered inappropriate in elderly diabetes management.

Metiglinides are short-acting insulin secretagogue agents, that enhance early phase of insulin secretion at meals, lowering postprandial glucose levels. They present lower risk of hypoglycemia than sulfonylureas, since their activity is dependent on the presence of glucose Repaglinide is the most effective agent of this class, with a moderate effect on weight gain.

Use of repaglinide may be indicated for elderly patients with type 2 diabetes because of the low risk of hypoglycemia, high efficacy on postprandial hyperglycemia, and safe use in renal impairment Dipeptidyl peptidase 4 DPP-4 inhibitors belong to the class of incretin enhancer agents.

They inhibit the DPP-4 enzyme, thereby extending the life-time of GLP-1 and increasing insulin secretion in a glucose dependent manner. Drugs in this class are generally well-tolerated in older people, with neutral effect on body weight and very low risk of hypoglycemia 66 , DPP-4 inhibitors have proven to be effective in reducing baseline HbA1c levels and fasting plasma glucose Moreover, a study of 80 elderly diabetic patients treated with oral glucose-lowering drug DPP4-inhibitors or sulfonylureas for at least 24 months showed that patients using DPP-4 inhibitors had better sarcopenic parameters fat-free mass, skeletal muscle mass, and related indices, muscle strength, and gait speed as compared with those receiving sulfonylureas The cardiovascular safety of this class of agents has been confirmed by several randomized controlled trials 70 — Alogliptin, saxagliptin, sitagliptin, and linagliptin 70 — 74 have proven to neither increase nor decrease risk of the combined major adverse cardiovascular events MACE in type 2 diabetic patients with established cardiovascular disease.

In the EXAMINE trial, patients with type 2 diabetes and recent acute coronary syndromes assigned to alogliptin had an increased, although non-statistically significant, rate of HF hospitalization when compared to the placebo group Moreover, data from the TECOS trial report that sitagliptin is not associated with a higher fracture risk, major osteoporotic fractures, or hip fractures Therefore, DPP-4 inhibitors may be considered as an effective and safely treatment option for older patients with type 2 diabetes Sodium-glucose cotransporter 2 SGLT-2 inhibitors are the latest marketed oral anti-hyperglycemic agents in diabetes management.

Beyond glucose lowering efficacy, SGLT-2 inhibitors have also beneficial effects in reducing body weight and blood pressure. If SGLT-2 inhibitors are used in combination with diuretics, lowering the dose of diuretics is needed to minimize the risks of hypotension and dehydration SGLT2-inhibitors are generally well-tolerated in older adults, except for increased risk of mycotic genital infections in both sexes.

There is evidence from cardiovascular outcome trials 80 , 81 that this class has beneficial effects in reducing the composite endpoint of cardiovascular deaths, non-fatal myocardial infarction and non-fatal stroke as compared with placebo in patients with type 2 diabetes and high cardiovascular risk.

Similarly, in the multinational, observational CVD-REAL study, new users of empaglifozin, canaglifozin, and dapaglifozin reported lower risk of cardiovascular mortality, MACE and hospitalization for heart failure as compared with new users of other glucose-lowering drugs Moreover, a subgroup analysis of the EMPA-REG OUTCOME study showed a significant reduction in the risk of MACE especially in patients older than 65 years treated with empaglifozin Based on these results, ADA and EASD recommend their use in patients with established or at high risk of cardiovascular disease In the respective RCTs designed to test the efficacy and safety of SGLT-2 inhibitors on renal outcomes 83 , 84 , both empagliflozin and canagliflozin use was associated with reduced risk of sustained loss of kidney function, attenuated GFR decline, and a reduction in albuminuria, which supports a possible renoprotective effect of this drugs in people with type 2 diabetes.

Conversely, on May the Food and Drug Administration released a warning relative to an increased risk of diabetic ketoacidosis DKA associated with use of SGLT-2 inhibitors 86 , on the basis of a comparative evaluation with DPP-4 inhibitors on a cohort of more than , type 2 diabetic patients The increased incidence of DKA related to SGLT2-inhibitors may be probably related to the non-insulin-dependent glucose clearance, hyperglucagonemia, and volume depletion Therefore, although this class has many beneficial effects on cardiovascular and renal outcomes, caution is needed using SGLT2 inhibitors in elderly because of increased risk of genital infections, dehydration, orthostatic hypotension, lower extremities amputations, and bone fracture 89 , Glucagon-like peptide 1 receptor agonists GLP-1RAs are innovative and pleiotropic drugs that act by promoting insulin secretion and reducing glucagon secretion in a glucose dependent manner and favoring weight loss.

As they use the injectable way of administration, they require neuro-psychological and physical integrity. GLP-1RAs are highly effective in lowering glucose levels, with minimal risk of hypoglycemia 91 , The main adverse effects associated with GLP-1RAs use consist of nausea, vomiting, diarrhea, and an increase in heart rate Furthermore, there is strong evidence from RCTs 95 — 97 that these drugs can reduce the risk of MACE in type 2 diabetic patients with high cardiovascular risk.

Results from preclinical studies showed also favorable effects of GLP-1RAs on neuronal protection and cognitive performances 98 , Randomized controlled trials assessing effects of incretin therapy on cognitive function and Alzheimer's disease in humans are currently ongoing.

If these benefits will be confirmed, use of GLP-1RA may be a helpful option even in patients with mild cognitive impairment.

Free and fixed-ratio combinations of GLP-1RAs and basal insulin formulations have been approved by regulatory agencies to potentiate antihyperglycemic effects and glycemic control in type 2 diabetic patients 57 , At the moment, two fixed-ratio combinations, insulin glargine plus lixisenatide IGlarLixi and insulin degludec plus liraglutide IDegLira , have been approved for treatment of type 2 diabetes A recent analysis compared effectiveness of fixed-ratio combination iGlarlixi vs.

IGlarLixi was associated with significantly higher HbA1c reductions, weight loss and number of patients reaching HbA1c target despite lower insulin doses, with similar rates oh hypoglycemic events and lower rates of gastrointestinal adverse events.

A meta-analysis of 26 RCTs have shown a mean reduction of 0. Moreover, when compared with intensive insulin therapy, either free or fixed combination of GLP-1RA and basal insulin led to a greater mean decrease of 0. Based on this evidence, combination strategies, either free or fixed, represent a good option for intensifying basal insulin therapy in patients with type 2 diabetes who need amelioration of glycemic control, without increasing the risk of hypoglycemia and weight gain Insulin remains the most effective drug for type 2 diabetes The main limitations of insulin therapy are the risk of hypoglycemia and weight gain, although it can be administered at any GFR value.

Insulin therapy requires patients' autonomy, intact visual, motor, and cognitive ability in diabetes management Since its discovery in , several and innovative insulin formulations have been developed. Insulin glargine U or U , degludec U or U , and detemir represent long acting insulin analogs which provide daily basal insulin profiles Compared with human insulin neutral protamine Hagedorn NPH , long-acting insulin analogs have a longer duration of action and a fatter pharmacokinetic profile, with a reduced risk of hypoglycemia Therefore, the newer basal insulins should be preferentially used in diabetic elderly, where they may be indicated as starting insulin therapy.

Prandial rapid aspart, lispro, glulisine and ultra-rapid acting faster aspart insulin analogs used at mealtime can be combined with basal insulin to sooner improve and intensify glycemic control However, both basal and prandial insulin require frequent titration to achieve the best anti-hyperglycemic effects.

Patients on enteral or parenteral nutrition may require frequent glucose monitoring intervals of 4—6 h to better titrate the insulin dose and to avoid hypo- and hyperglycemic events Caution is needed in insulin titration because a simple error can easily precipitate major hypoglycemic episodes, leading to falls, and bone fractures Alternatively, premixed insulin regimen, eliminating the challenge of mixing insulin, may have a role in elderly patients who have regular eating habits, with similar efficacy as compared with basal bolus therapy Therefore, use of insulin therapy in elderly patients often requires the assistance of a caregiver if patients' abilities are limited.

Older adults with type 2 diabetes represent a complex and heterogenous age group. Managing diabetes in older age remains an important clinical challenge for all physicians, either primary care providers or specialists.

A comprehensive geriatric assessment should be performed at diagnosis of diabetes to better understand cognitive, visual and motor abilities, and coexisting comorbidities. In the choice of anti-hyperglycemic strategies, drugs with proven tolerability, safety, and minimal hypoglycemic risk should be preferred.

Anti-diabetes treatment regimens in elderly must be simple, sustainable, and safe to best mirror patients' preferences, wishes, and needs. GB, MIM, KE, and DG conceived the manuscript. ML, GB, and MIM drafted the manuscript. JM, KE, and DG reviewed and edited the manuscript.

All authors gave the approval to the final version of the manuscript. MIM received a consultancy fee from MSD and has held lectures for Sanofi, Astrazeneca, and Novo Nordisk.

JM has held lectures for Astra Zeneca, Boehringer-Ingelheim, Eli Lilly, MSD, Novo Nordisk, Sanofi, and Servier and received research support from Boehringer-Ingelheim, MSD, Novo Nordisk, Sanofi.

A thoracotomy was performed in the left fifth intercostal space, and the pericardium was opened. A Prolene ligature was placed around the proximal left anterior descending coronary artery in the area immediately below the left atrial appendage.

The ends of the suture were threaded through a propylene tube to form a snare. Coronary artery occlusion was performed by clamping the snare onto the epicardial surface with a hemostat, and occlusion was confirmed by the appearance of epicardial cyanosis and ST elevation on electrocardiography.

Reperfusion was achieved by loosening the snare and was verified by observing an epicardial hyperemia Figure 1. Experimental protocol. Rats were divided into three groups according to their age 3, 10—12, and 22—24 months of age. Rats in c and d underwent 45 minutes of ischemia followed by minutes of reperfusion.

The rats were instrumented for the measurement of systemic hemodynamics as previously described Hemodynamic data were continuously recorded on a data-acquisition system Power Lab; ADInstruments, Colorado Springs, CO. Briefly, heparin-filled catheters were inserted into the right jugular vein and right carotid artery for fluid administration and measurement of mean arterial pressure, respectively.

This pressure—volume catheter was inserted to measure the left ventricular ejection fraction LVEF. Heart rates were also monitored For determining infarct size, regional ischemia was induced for 45 minutes by tightening a snare around the left anterior descending coronary artery, followed by minutes of reperfusion.

Then after retightening the snare, 0. Then the hearts were sectioned into 4 or 5 cross-sectional pieces of 2-mm thickness, and the pieces were incubated at 37°C for 15 minutes in triphenyltetrazolium chloride solution TTC in 0.

TTC reacted with intracellular dehydrogenases and formed a brick-red-colored precipitate, leaving the dead tissue off-white. Thereafter, the infarcted and non-infarcted myocardium within the anatomical areas at risk were separated and weighed. Infarct size was expressed as a percentage of the anatomical area at risk 20 , Thereafter, the homogenates were centrifuged at 12, rpm for 30 minutes at 4°C.

Protein concentration was determined using a modified Bradford assay Bio-Rad Laboratories, Hercules, CA using bovine serum albumin as a standard. Equal volumes of the heart homogenate were added to Laemmli buffer Bio-Rad Laboratories and denatured by heating to °C for 5 minutes.

The primary antibodies were visualized by using the EZ-Western Lumi Femto Kit DOGEN, Seoul, Korea and using appropriate secondary antibodies conjugated to horseradish peroxidase. Statistical analyses were performed using IBM SPSS Statistics for Windows, Version All results were expressed as mean ± standard deviation SD.

Values of p less than. Body mass was ± 19 g in young rats, ± 43 g in middle-aged rats, and ± 43 g in old rats. Blood glucose levels were significantly higher in the HG group than in the NG group see Supplementary Table 1. Acute hyperglycemia worsened the reduction of the LVEF after ischemia-reperfusion injury in all age groups Figure 2.

Changes in the LVEF after ischemia-reperfusion injury. No significant differences in anatomical area at risk were observed among the groups Figure 3. Hyperglycemia increased the infarct size in young and middle-aged rats, but not in old rats. Myocardial infarct size.

a Representative pictures of left ventricular sections after triphenyltetrazolium chloride solution staining. b Infarct size expressed as a percentage of the left ventricular area and area at risk, respectively. Figure 4 shows the expression of proteins related to apoptosis after ischemia-reperfusion injury under normoglycemia and hyperglycemia according to the age groups.

The expression of proteins related to apoptosis. a — c C-PARP; d — f Bcl-2; g — i Bax; j — l cytochrome c. Data are shown as mean ± SD. The expression of proteins related to autophagy. a — c Bnip3; d — f Beclin-1; g — i Atg5; j — l LC3B-II.

In this preclinical study addressing the age-related differences in the impact of hyperglycemia on myocardial ischemia-reperfusion injury, we demonstrated less impact of acute hyperglycemia on the infarct size in old rats than in young and middle-aged rats.

However, the reduction of ejection fraction after ischemia-reperfusion injury was aggravated by acute hyperglycemia in all age groups. The altered expression of proteins related to apoptosis and autophagy caused by acute hyperglycemia after ischemia-reperfusion injury was not evident in old rats.

Several experimental studies have shown that acute hyperglycemia increases the susceptibility to myocardial ischemia-reperfusion injury 4—6.

In this study, acute hyperglycemia increased the infarct size in young and middle-aged rats. However, the infarct size in old rats was similar under normoglycemia and hyperglycemia. Studies on the age-related differences in the effect of hyperglycemia on ischemia-reperfusion injury are scarce. A previous study addressed that aged, diabetic rats were more susceptible to sublethal ischemia than were younger diabetic rats Therefore, the strength of our study was that it compared the effect of acute hyperglycemia on ischemia-reperfusion injury with aging.

Acute hyperglycemia aggravated the functional decline expressed as the reduction of the LVEF after ischemia-reperfusion injury in all age groups, even though the HG effect on myocardial infarct size was attenuated in old rats.

A previous study revealed that older patients do not have larger infarcts, even though both advanced age and infarct size were associated with higher mortality 22 , From this result, we can infer that the functional decline in the old heart, irrespective of infarct size, might be correlated with a poor prognosis.

Ventricular function is determined by infarct size and residual function of the spared myocardium. Further, the myocardial perfusion reserve had a stronger correlation with the LVEF than with infarct size Even in a previous clinical trial, a negative linear relationship was observed between infarct size and the LVEF in patients with moderate-to-large infarcts Taken together, these findings suggest the need to estimate the ventricular function in addition to infarct size when evaluating myocardial ischemia-reperfusion injury.

Furthermore, it can be a possible explanation for the discrepancy between the change in infarct size and LVEF according to the different age groups.

Myocardial ischemia reperfusion injury was reported to be related to apoptosis and autophagy 12 , Apoptosis is programmed cell death and removal without activation of an inflammatory process, based on DNA and cellular fragmentation A previous study revealed increased plasma apoptotic marker levels in elderly patients than in adult patients and higher myocardial apoptotic ratio in older rats, thereby suggesting that aging exacerbated myocardial ischemia-reperfusion injury in humans and rats 8.

Several studies have reported increased or decreased autophagic protein expression with aging 26 , We investigated the expression of apoptotic and autophagic proteins according to the different age groups in both normoglycemia and hyperglycemia.

In accordance with the age-related differences in the impact of acute hyperglycemia on infarct size, the expression of proteins related to apoptosis or autophagy Bnip3, Beclin-1, Atg5, and LC3B-II after ischemia- reperfusion injury was not different between acute hyperglycemia and normoglycemia in old rats, which was significantly different from that in young or middle-aged rats.

C-PARP is an abundant DNA-binding enzyme that detects and signals DNA strand breakages The presence of C-PARP is used to detect apoptosis in many cell types A previous study conducted in a rat model of aging-associated cardiovascular dysfunction demonstrated that acute inhibition of PARP by a PARP inhibitor decreased the age-related myocardial and vascular PARP activation, resulting in the improvement of left ventricular contractility and enhanced endothelium-dependent vasorelaxation This result indicates that C-PARP is a consequence of apoptosis and is associated with cardiovascular dysfunction following aging.

Although significant differences were observed in C-PARP expression between normoglycemia and hyperglycemia among the different age groups, no age-related differences in C-PARP expression were observed between normoglycemia and hyperglycemia after ischemia-reperfusion injury.

Acute hyperglycemia exaggerated the increased expression of C-PARP by ischemia-reperfusion injury in all age groups, which correlated with the functional decline of the left ventricle. Bcl-2 is a well-known inhibitor of apoptosis The overexpression of Bcl-2 in transgenic mice effectively reduced myocardial ischemia-reperfusion injury 32 , In a previous study, aging decreased antiapoptotic Bcl-2 levels Acute hyperglycemia reduced Bcl-2 expression only in middle-aged rats.

Bax is a proapoptotic protein that is upregulated in response to chronic pressure overload and cardiomyocyte-specific apoptosis Bax showed age-associated differences in rats that underwent coronary artery occlusion Old rats exhibited higher levels of Bax at baseline and greater decline of Bax after coronary artery occlusion than did young rats in that study.

However, unlike in the previous report, we found that Bax expression was elevated after ischemia-reperfusion injury.

This discrepancy might be due to differences in the experimental design. A previous study elucidated the change in Bax protein after coronary artery occlusion, whereas we compared the expression of Bax between the control group and after ischemia-reperfusion injury.

The relationship between age and Bax expression under hyperglycemia has not been extensively characterized. In our study, we found that hyperglycemia did not alter the level of Bax after ischemia-reperfusion injury to a greater extent in middle-aged and old rats than in young rats.

Mitochondrial cytochrome c release initiates apoptosis A previous study demonstrated that mitochondrial cytochrome c release was associated with hyperglycemia-induced myocardial apoptosis However, age-related differences in the release of cytochrome c under hyperglycemia have not been elucidated before.

The differences in the expression of cytochrome c induced by ischemia-reperfusion injury under different glycemic conditions were evident only in young rats. Middle-aged and old rats did not show significant differences in cytochrome c expression between normoglycemia and hyperglycemia after ischemia-reperfusion injury.

Furthermore, the expression of cytochrome c was similar between normoglycemia and hyperglycemia in old rats. Although the expression of proteins related to apoptosis did not show identical patterns, a trend of age-related differences in the expression of these proteins was observed between normoglycemia and hyperglycemia after ischemia-reperfusion injury.

These results support the different pattern of infarct size changes according to the different age groups. Bnip3 is a hypoxia-regulated member of the Bcl-2 family of proteins that is implicated in apoptosis, programmed necrosis, autophagy, and mitochondrial autophagy 39 , A previous study demonstrated that Bnip3 induced postischemic apoptosis 41 and diabetes-induced Bnip3 expression compromised cardiac cell survival and cardiac function Moreover, the upregulation of Beclin-1 by ischemia-reperfusion injury stimulated autophagy 43 and the activation of Beclin-1 type 2 diabetes increased cardiomyocyte autophagy In the current study, the expressions of Bnip3 and Beclin-1 increased with ischemia-reperfusion injury under normoglycemia and hyperglycemia in all age groups.

Further, hyperglycemia intensified the increased expression of Bnip3 and Beclin-1 with ischemia-reperfusion injury in the young and middle-aged hearts, but not in the old hearts. These age-related differences in Bnip3 and Beclin-1 expressions under hyperglycemia paralleled the differences in myocardial infarct size according to age.

Cardiac-specific loss of Atg5 caused cardiomyopathy in mice Another study demonstrated that silencing Atg5 aggravated cardiac hypertrophy Thus, the upregulation of autophagy may be an adaptive response for protecting cells Atg5 was also upregulated by hyperglycemia and ischemia-reperfusion injury in the current study.

Moreover, this upregulation of Atg5 showed age-related differences. The impact of hyperglycemia on ischemia-reperfusion injury was prominent only in middle-aged rats.

The expression of LC3B-II, an autophagy-associated protein, was increased during reperfusion in fibrillated mouse hearts than in non-fibrillated mouse hearts Accordingly, the expression of LC3B-II was increased in hyperglycemia and after ischemia-reperfusion injury.

These upregulated expressions also exhibited age-related differences, such that the upregulation in hyperglycemia, rather than in normoglycemia, after ischemia-reperfusion injury was only seen in middle-aged rats.

Taken together, these findings suggest the presence of age- associated differences in the impact of hyperglycemia on myocardial ischemia-reperfusion injury. In addition, possible related mechanisms, such as apoptosis and autophagy, were elucidated.

A trend was also observed toward a lesser impact of acute hyperglycemia after ischemia-reperfusion injury on infarct size as well as apoptotic and autophagic protein expression in old rats. These results suggest that we need to control blood glucose levels in patients with coronary artery disease according to their age.

Although the benefits of glycemic control are well established in reducing the risk of microvascular disease, the possibility of acute hypoglycemia increases with tight glycemic management, especially among elderly patients.

The disappointing results of recent clinical trials on tight glycemic control in elderly patients with type 2 diabetes highlight the potential cardiovascular risks of hypoglycemia and hyperglycemia; hence, hypoglycemia as a risk factor for poor prognosis is a topic of increasing interest 1 , 48— This study has several limitations.

The focus of this experiment was on evaluating the age-related differences in protein expression associated with apoptosis and autophagy. Although our results demonstrated age-associated differences in protein expression, the relationship between cardiac functions, such as hemodynamics and ventricular response, and protein expression might be ambiguous.

Second, the interaction between apoptosis and autophagy was not investigated. Previous studies addressed the regulation of interplay between autophagy and apoptosis We demonstrated that acute hyperglycemia aggravated myocardial ischemia-reperfusion injury in young and middle-aged rats.

The effect of acute hyperglycemia on myocardial ischemia-reperfusion injury was attenuated in old rats. This heterogeneity paralleled the attenuation in apoptotic and autophagic signaling proteins, such as Bcl-2, Bnip3, and Beclin-1, in the aged myocardium.

We suggest that the value of acute hyperglycemia as a risk factor for myocardial ischemia-reperfusion injury is less in the aged myocardium, possibly because of the differential activation of apoptotic and autophagic signaling. This finding may have clinical implications regarding the strategy of glucose control in patients with myocardial infarction according to their age.

Assistance with the study was provided by Ji-Hae Jun and Eun-Jung Shin, from Anesthesia and Pain Research Institute, Yonsei University College of Medicine.

Kosiborod M , Inzucchi SE , Krumholz HM , et al. Glucometrics in patients hospitalized with acute myocardial infarction: defining the optimal outcomes-based measure of risk. Ready to take the first step? Start with our quiz to see how Nutrisense can support your health.

How It Works Nutritionists Journal. What Is A CGM? Get Started. Promo code SPRING will be automatically applied at checkout! The Effect of Aging on Your Blood Glucose Levels.

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