How to cite this article:Kalra S, Mukherjee JJ, Venkataraman S, Bantwal G, Shaikh S, Saboo B, Das AK, Ramachandran A. How to cite this URL:Kalra S, Mukherjee JJ, Venkataraman S, Bantwal G, Shaikh S, Saboo B, Das AK, Ramachandran A.
Near the end of August, 2006, I cooked what would be the last homemade fetuccini alfredo I'd ever make.
November is American Diabetes Month, among much else (including National Novel Writing Month and National Pomegranate Month, according to Wikipedia). Things didn't improve in college, where my idea of cooking was to boil some pasta and cover it in Teriyaki sauce, poach chicken in ranch dressing, or simply heat up a can of Chef Boyardee. Fat was not something I enjoyed being, but I rationalized my poor health as a defining characteristic of being me; if I were to suddenly start eating broccoli, quit smoking, and stop shoving carbs down my throat, I would cease to exist as myself. I'd be remiss, though, if I didn't mention my suspicion that I was already showing symptoms when I moved up to Maryland. I bring this up because, if there's one lesson I want people to take away from my story, it is this: if you have even the slightest suspicion that you may be diabetic, it doesn't hurt to have your blood checked. At the same time, I was working a job that required some manual labor--lifting furniture and such--and I used that to increase the amount of exercise I was getting. All this talk of the short-term complications shouldn't distract you from the fact that the long-term ramifications are also scary. But I don't want to scare you too much, because truth be told, being diagnosed with diabetes is one of the best things that ever happened to me.
The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Repeated episodes of hypoglycemia can adversely affect defense mechanisms against falling blood glucose, resulting in significant morbidity and mortality which is reportedly associated with a six-fold increase in death. The study also reported increased rates of hypoglycemia in those with longer duration of insulin treatment. The purpose of this review is to discuss the importance of hypoglycemia in the management of patients with DM, with an aim to improve understanding of the risk factors, impact and consequences of hypoglycemia.
While recent progress related to prevention of hypoglycemia including patient education strategies and the use of newer therapeutic agents with a lower risk for hypoglycemia aim at achieving and maintaining optimal glycaemic control, hypoglycemia still remains a major challenge which needs to be addressed for better management and treatment of patients with diabetes. Iatrogenic hypoglycemia associated with diabetes medications are among the most common causes of hypoglycemia in patients with diabetes. Hypoglycemia may also result from certain seldom causes such as pancreatic or non-islet cell tumors, autoimmune conditions, organ failure, endocrine disease, inborn errors of metabolism, dietary toxins, alcohol consumption, stress, infections and miscellaneous conditions (such as sepsis, starvation, severe excessive exercise). Overall, insufficient food consumption was the most common cause identified for severe hypoglycemia (43% in T1DM and 47% in T2DM).
Other causes included physical exercise (24% and 23%), insulin dose miscalculation (24% and 16%), stressful situations (12% and 17%), oscillating blood glucose levels (9% and 8%) and impaired hypoglycemia awareness (8% and 5%) in T1DM and T2DM, respectively.
The most important risk factor for the occurrence of hypoglycemia is the aggressiveness of therapy applied to achieve glycemic control. An increased incidence of severe hypoglycemia with intensive glucose control therapy has been clearly demonstrated in several RCTs including DCCT, UKPDS, Treat-to-target trial (4-T), ADVANCE, ACCORD and VADT. The common risk factors for hypoglycemia in elderly patients has been summarized in [Table 3]. Hypoglycaemia unawareness is associated with a 6-fold and 9-fold increased risk of severe hypoglycemia in patients with T1DM and T2DM, respectively. Impaired cognitive function can have potentially deleterious and cumulative long-term effects on intellectual function, particularly in young children.Hypoglycemia and the brainGlucose is the metabolic fuel for the brain. Acute interruption of glucose supply may result in functional brain failure and eventually lead to coma and death.
There is a possible association between repeated episodes of severe hypoglycemia and long term cognitive dysfunction.
Acute hypoglycemia provokes sympatho-adrenal activation and release of epinephrine which in turn stimulates hemodynamic changes by increasing cardiac rate and peripheral systolic blood pressure, reducing central blood pressure and peripheral arterial resistance and by increasing myocardial contractility, stroke volume and cardiac output. In non-diabetic people, acute hypoglycemia is associated with a decline in arterial wall stiffness but in people with diabetes of long duration, arterial wall stiffness as such is greater and arteries are less elastic in response to hypoglycemia, manifesting in a lesser fall in central arterial pressure.

The decreased elasticity of arterial walls also accelerates the return of the reflected wave causing its earlier arrival during late systole.
However, there have been case reports associating myocardial infractions with hypoglycemia. Furthermore, inflammatory cytokines like IL-1 have also been shown to increase the severity of hypoglycemia, thus perpetuating a positive feedback cycle [Figure 1]. Animal studies and in-vitro studies, have reported that a decrease in glucose concentrations was associated with reductions in retinal sensitivity, [72] reduced viability of all retinal cell types, [73] retinal cell death, [74] loss of vision, reduction of retinal responses, increased retinal degeneration [75] and cone cell death. Recurrent hypoglycemic episodes generate feelings of powerlessness, anxiety, and depression amongst patients and their families. Diurnal hypoglycemic events however, did have a significant negative impact on overall treatment satisfaction. These events are more easily identified and bothersome to daily functioning compared with nocturnal events. As evident from a simulator performance study, during episodes of hypoglycemia in patients with T1DM result in impaired task performance like driving across the midline and speeding. Various factors that contribute to a higher probability of hypoglycemia-related driving mishaps include increased episodes of hypoglycemic blankness, less frequent self-monitoring blood glucose (SMBG), subcutaneous administration of insulin, greater carbohydrate utilization [85] besides mood changes, irritability and anger which impairs rapid decision making, sustained attention, analysis of complex visual stimuli and hand-eye coordination. At the annual examination by an independent consultant diabetologist, 3 m of blood glucose readings must be available.
In a prospective, survey for a year of 243 diabetic patients treated with insulin, it was found that 30% episodes of mild, and 11% episodes of severe hypoglycemia occurred at work. A positive correlation has been observed between reduced productivity and increased health care costs associated with hypoglycemia among patients with T1DM or T2DM. In order to mitigate and manage the risk of hypoglycemia at workplace, planned action like counseling and expert medical advice should be included. Respondents who experienced a nocturnal NSHE, 22.7% reported arriving late for work or miss a full day of work. Nocturnal NSHEs also resulted in a missed meeting or work appointment or not finishing work on time among 31.8% of the respondents. Hypoglycemia during exercise may also result from impaired release of counter-regulatory hormones caused by a previous episode of hypoglycemia.
Consequently, patients with T1DM who experience hypoglycemia on days preceding the final competitive event are at an increased risk on the day of the actual event due to an autonomic counter-regulatory failure during exercise. Almost all individuals who travel long distances are subjected to physiological symptoms such as include insomnia, daytime somnolence, fatigue, stress, anorexia, nocturia, gastrointestinal discomforts, muscle aches and headaches [108] and psychological disturbances such as depressed mood, irritability, apathy, malaise, difficulty in concentrating, and decrements in both mental and physical performance [109] that may profoundly impair the decision making power of an individual. It is a significant barrier in terms of adherence to medication and achieving normoglycemia with intensive therapy.
Fear of hypoglycemia, an additional psychological burden that patients with T2DM experience can limit the aggressiveness of drug therapy resulting from reduced patients' willingness to take medication as directed. Hypoglycemia was associated with significantly poor QoL and reduced treatment satisfaction.
A patient who experiences an episode of hypoglycemia for the first time will often refer to that event as being "severe" because of the fear that they might become powerless to prevent their own morbidity without outside assistance. For the purpose of developing a clinical scoring system, awareness of hypoglycemia has been arbitrarily classified into 3 broad categories.
Higher incidence of hypoglycemia, particularly among patients treated with insulin over extended periods of time, reinforce the idea that disease progression and increased insulin use subsequently increases the risk of hypoglycemia with clinical consequences ranging from mild discomfort to coma and even death.
A meta-analysis of 21 studies comparing glyburide with other anti-diabetic medications, including insulin, revealed a 83% higher risk of hypoglycemia with glyburide compared with other sulfonylureas while the risk of hypoglycemia was 52% higher when compared with those taking other insulin secretagogues.
However, studies have shown that the risk of hypoglycemia with repaglinide was similar to second-generation sulfonylureas. These programs should also educate patients about the importance of frequent SMBG, good record keeping and regular follow-up with their primary care physicians.
Interventions targeting health beliefs and attitudes about hypoglycemia and diabetes self-management can be more effective than knowledge-centered patient education, which focus on "symptom perception" in reducing hypoglycemia unawareness.
Glucose monitoring can be done either by periodic self-monitoring of capillary blood glucose or by continuous glucose monitoring (CGM). In order to uncover hypoglycemia unawareness or high-risk patterns, periodic 7-point profile testing should be performed.

Consistent with their mechanisms of action, glucose-lowering agents can be broadly categorized as those having either a low- or a high-risk of hypoglycemia.
As discussed earlier, agents that comprise the high-risk category include insulin, sulfonylurea and meglitinides, all of which increase the insulin level in a glucose-independent manner. NPH insulin is a crystalline suspension of insulin with protamine and zinc that releases insulin at slower rate, providing intermediate-acting insulin with slow onset of action and longer duration of action than regular insulin.
However, due to variable absorptions and peaks, most patients on this regimen experience early morning hypoglycemia. Following once daily administration, both insulin glargine and detemir demonstrate a flat insulin profile that more closely matches endogenous insulin secretion.
Evidence from studies indicate that patients treated with insulin glargine experience a 46% reduction in severe and 59% reduction in nocturnal hypoglycemia, compared with those treated with NPH insulin, [139] while use of insulin detemir was associated with a significant reduction in the risk of nocturnal hypoglycemia compared with NPH insulin.
Bolus requirement are met by insulin preparations such as insulin lispro, insulin aspart, and insulin glulisine, which have a rapid onset, and shorter duration of action, thus reducing postprandial blood glucose excursions and the risk of hypoglycemia in the periods between meals. Insulin glulisine provides improved glycemic control with comparable symptomatic hypoglycemia versus regular human insulin (RHI) in the outpatient setting and may be considered a better choice than RHI in non-critically ill hospitalized patients. A meta-analysis of 22 RCTs confirmed that both HbA1c level and the rate of severe hypoglycemia were significantly lower during CSII compared with MDI. Recent non-randomized clinic trial reports have demonstrated that improved glycemic control can be achieved without an increased risk for severe hypoglycemia when patients are switched from MDI to CSII therapy.
Incretins are gastrointestinal hormones that stimulate postprandial release of insulin from β-cells in glucose dependent manner ("incretin effect").
The incretin system can be pharmacologically influenced through GLP-1 analogues and DPP-4 inhibitors. GLP-1 analogues are injectable peptides that act as agonists of the GLP-1 receptor, which are more resistant to DPP-4 and so have longer action than human GLP-1.
While DPP-4 inhibitors are oral agents that prolong the activity of endogenously released GLP-1 and GIP by inhibiting the DPP-4 enzyme. They have the advantage of an extremely low hypoglycemic risk because of their glucose-dependent action.
Glucagon may be considered for use in T2DM patients with advanced disease and receiving intensive insulin therapy [163] while it should be avoided in patients on sulfonylureas.
They should also be advised on the importance of avoiding any delay in treating the patient experiencing hypoglycemia and measures to be taken to restore normal blood glucose levels should be considered.Treatment of hypoglycemiaA conscious patient with hypoglycemia should be treated with oral administration of 15-20 grams of carbohydrate (4 teaspoons of sugar or glucose).
This should be followed by a SMBG 15 minutes later and the treatment should be repeated if hypoglycemia is persisting. The patient should be advised to eat a regular meal or have a snack to prevent recurrence of hypoglycemia. If a patient is unconscious and unable to accept food orally, immediate administration of intravenous glucose is necessary; alternatively glucagon may be administered intramuscularly at home by a family member. Treatment should be modified in the event of hypoglycemia occurring repeatedly at a particular time of the day or in the event of hypoglycemia unawareness.
Mild hypoglycemia reduces QoL, while severe hypoglycemia is life-threatening and can precipitate major cardiovascular and cerebrovascular events. Careful attention should be paid while deciding upon a treatment regimen for the management of diabetes such that adequate glycemic control measures can be implemented against the life-threatening complication of hypoglycemia. To improve diabetes-related outcomes, including reducing the risk and consequences of hypoglycemia, effective patient education is essential. Physician-patient collaboration is vital to develop and modify a treatment plan that is acceptable to the patient. The use of newer antidiabetic medications with little or no risk of hypoglycemia will reduce the future risk of hypoglycemia. Empowering patients with the tools to monitor hypoglycemia, making them aware of the risks of hypoglycemia and the available preventive strategies, together with an individualized plan of treatment, can decrease the frequency and severity of hypoglycemia.

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