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DOI: 10.1177/0145721706294259 © 2006 American Association of Diabetes Educators; Published by SAGE Publications
Insulin Treatment and the Problem of Weight Gain in Type 2 DiabetesFrom the Joslin Diabetes Center, Boston, Massachusetts. Correspondence to Catherine Carver, MS, APRN, BC, CDE, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215 (cathy.carver{at}joslin.harvard.edu).
Purpose Insulin therapy has been shown to benefit the prognosis in patients with type 2 diabetes, but its initiation and intensification is often delayed through concerns about hypoglycemia and weight gain. In addition, weight gain is linked to the pathophysiology of type 2 diabetes and contributes to the overall risk for adverse cardiovascular outcomes. This article attempts to summarize this issue and examine the options available for weight management. Methods A broad range of literature has been reviewed to distil important, consistent facts about insulin and weight gain and the options available for limiting the problem. Results Unfortunately, the great benefits of insulin therapy may be potentially undermined by weight gain. Weight gain is physiologically and psychologically undesirable, especially in patients with diabetes who are already overweight. The fear of weight gain with some medications contributes to psychological insulin resistance, which may discourage patients from commencing or following insulin regimens. However, new diabetes treatments and lifestyle interventions can be used to mitigate these problems. Conclusions The exact choice of insulin and oral medications and weight loss interventions are important considerations in the overall management of patients with type 2 diabetes. Changes in a patient's lifestyle, such as modifications todiet and implementing an exercise program, are first-line treatments for type 2 diabetes and can also counteract insulin-induced weight gain.
In recent years, the incidences of both type 2 diabetes1,2 and obesity3 have reached pandemic proportions. The prevalence of diabetes worldwide was recently estimated to be 171 million (2.8%) in 2000 and may rise to 366 million (4.4%) by 2030.2 More than 1 billion adults are estimated to be overweight globally, with 300 million of them being clinically obese.4 The increased consumption of high-calorie, high-saturated fat, and low-nutrient foods, coupled with reduced physical activity, has been blamed for the vast increase in obesity rates across the world, and obesity poses a major risk for serious diet-related diseases, including type 2 diabetes. Studies into these 2 phenomena suggested that the concurrent increase in both disorders is not a coincidence. Body mass index (BMI), abdominal fat distribution, and weight gain are all important risk factors for developing type 2 diabetes. Data from the 1999-2000 US National Health and Nutrition Examination Survey, indicated that two thirds of adult men and women diagnosed with type 2 diabetes have a BMI of 27 kg/m2 or greater.5 Moreover, the risk of diabetes increased with increasing BMI; the incidence of diabetes was 2% in those classed as overweight (25-29.9 kg/m2), 8% in class 1 obesity groups (30-34.0 kg/m2), and 13% in class 2 to 3 obesity groups (>35 kg/m2). In addition, weight gain during adulthood increased the risk of developing type 2 diabetes, even at relatively low levels of BMI in initially normal weight individuals.6,7 The life-time risk of acquiring type 2 diabetes is approximately 50% in individuals with morbid obesity, and there is evidence of a causal link between obesity and type 2 diabetes.7 Obesity—particularly abdominal obesity—promotes insulin resistance, which has been hypothesized to be one of the major factors behind the pathophysiology of type 2 diabetes. Pancreatic ß cells, which produce insulin, initially compensate to maintain normal glucose metabolism by increasing the amount of insulin secreted. However, in the presence of increasing insulin resistance, over time, the demand for insulin exceeds the ability to compensate, ultimately leading to pancreatic exhaustion and increased plasma glucose levels.8 The common complications associated with type 2 diabetes are classified as macrovascular (eg, coronary heart disease, peripheral vascular disease) and microvascular (eg, retinopathy, nephropathy, neuropathy). Coronary heart disease causes 70% of deaths in patients with type 1 and type 2 diabetes and is the main cause of excess mortality in individuals with diabetes.9 Diabetic retinopathy is a very common microvascular complication and often results in blindness. Indeed, it accounts for 11% of new cases of blindness in the United States each year.10 Diabetic nephropathy accounts for one third of all cases of end-stage renal failure in the United States11 and will result in the need for dialysis and kidney transplantation in these patients. Although diabetic neuropathy is rarely a direct cause of death, it is a major cause of morbidity. A common symptom of diabetic neuropathy is numbness, which pre-disposes the feet to ulcers, in a condition known as diabetic foot, and may lead to gangrene and amputation.
The BMI is a standard way to define weight. It is calculated by dividing the square of a patient's height in meters by the patient's weight in kilograms. An overweight BMI value is between 25 and 29.9 kg/m2; an obese BMI value is equal to or greater than 30 kg/m2. Another way of evaluating obesity is to look at the way fat is stored on a patient, particularly the waist and hips. A disproportionate amount of abdominal fat pre-disposes an individual to coronary heart disease.12,13 The waist-to-hip ratio (WHR) is calculated by dividing the waist measurement by the hip measurement. Ideally, women and men should have a WHR of 0.8 or lower and 1 or lower, respectively. Waist circumference is also an indicator of obesity.
Treatment of type 2 diabetes involves diet and exercise, oral agents, and insulin therapy. One oral antidiabetic agent, metformin (Glucophage®, Merck, Whitehouse Station, NJ), does not promote weight gain; therefore, the therapeutic use of metformin in combination with insulin is frequently recommended as a way of limiting weight gain in patients with type 2 diabetes.14,15 A large-scale trial showed that metformin treatment was associated with lower all-cause mortality and lower incidences of myocardial infarction and stroke, which may be due to less weight gain in these individuals.16 Insulin therapy involves multiple, but flexible, daily insulin injections that can be tailored to the individual's requirements. Several studies have indicated that early, intensive insulin therapy minimizes long-term complications in patients with diabetes.17-19 The United Kingdom Prospective Diabetes Study (UKPDS), an observational study in 4585 patients, showed that a reduction in hemoglobin A1C (a measure of long-term glycemic control) by 1% from insulin treatment resulted in a 37% mean reduction in risk of microvascular complications and a 14% mean reduction in risk for myocardial infarction in patients with type 2 diabetes.17 Likewise, the Kumamoto study19 showed that good glycemic control from insulin treatment delayed the onset and progression of diabetic retinopathy, nephropathy, and neuropathies in Japanese patients with type 2 diabetes. In addition, a cost-effectiveness analysis study, which used a computer simulation to estimate the lifetime benefit and costs of insulin therapy in a sample of 120 000 people with type 2 diabetes, has indicated that the lifetime improvement in quality and longevity of life derived from insulin therapy outweigh the cost of treatment.20 Consequently, insulin treatment is beneficial in both health and economic outcomes. Several studies have, however, revealed that the great benefits of insulin come at a price. An unfortunate consequence of insulin therapy is the increased frequency of an unacceptably low level of blood glucose (hypoglycemia) in a small number of patients. Hypoglycemia can cause unpleasant symptoms such as dizziness and nausea and, in severe cases, coma or death. As a result, it is an impediment to insulin therapy and may prevent many patients from gaining the benefits that treatment so clearly brings.
A further problem associated with intensive insulin treatment in patients with type 2 diabetes is excessive weight gain. Results from the UKPDS showed those who received insulin treatment gained, on average, 5 kg from the start of the study.16 Weight gain such as this may have deleterious consequences. It has been estimated that for every 1 kg of weight gain after high school, the risk of coronary heart disease increases by 5.7% for women and 3.1% for men, with adverse changes in lipid profile and blood pressure.21,22 Insulin-induced weight gain may also cause psychological burdens on individuals with type 2 diabetes, especially as an estimated 60% to 90% of the patients may be already overweight or obese.6,23 Such weight gain may frustrate patients who are trying to adhere to an exercise and diet regimen. Excessive weight gain has been shown to be a significant factor in the reluctance of both patients and health care professionals to initiate insulin therapy. This has been termed psychological insulin resistance.24 The Diabetes Attitudes, Wishes and Needs study examined the psychosocial issues in diabetes and found that more than half of the people with type 2 diabetes were worried about starting insulin; furthermore, a third of physicians postpone treatment until it is absolutely essential.25 In the more traditional sense, insulin resistance, as part of the pathophysiology of type 2 diabetes, can also be a problem in achieving good glycemic control. Patients with severe insulin resistance may require very high doses of insulin to reduce their hemoglobin A1C level, and this can be a barrier to initiating or intensifying insulin regimens.24 Diabetes is a chronic disease, and the burden of treatment and managing complications and issues such as weight gain can take a toll on the patient. It is now common for people with diabetes to be affected by major depression: studies have found that the prevalence of comorbid depressive and anxiety disorders is much higher in patients with diabetes than matched control groups and is up to 30% depending on assessment methods.26-28 This observation cannot be ignored as studies have shown that patients with diabetes and depression have poorer adherence to oral diabetes agents and other medication regimens, have more sedentary lifestyles, and do not eat healthily compared with nondepressed patients with diabetes.29,30 Depression in people with diabetes is also associated with higher hemoglobin A1C levels and obesity (BMI >30 kg/m2) compared with people with diabetes who are not depressed.31 Naturally, these associations are obstructive when insulin therapy is implemented or intensified in patients with diabetes and depression. Regardless of weight, it is thought that depression is associated with insulin resistance,32,33 which can be improved by antidepressant medication. Of course, this must be balanced against the observation that several anti-depressants cause weight gain and diabetes.34 Consequently, weight gain and depression are intricately linked in patients with diabetes, and steps to counteract both conditions must be taken. Managing a patient with type 2 diabetes and depression can often be seen as a conflict of interests, as treatments often result in weight gain. Weight gain worsens insulin resistance; thus, insulin dosages may have to be increased to achieve a sufficient therapeutic response. Physicians must therefore consider the implications of associated weight gain and take measures to offset this problem when prescribing insulin.
Several reasons have been suggested for the apparent weight increase from insulin therapy in type 2 diabetes, including fear of hypoglycemia, reduction of glucose loss in urine (glycosuria), the anabolic effects of insulin, and possible effects on the central nervous system.
As mentioned previously, a consequence of insulin treatment is the risk of hypoglycemia. However, the perceived threat of a hypoglycemic episode has been shown to greatly exceed the actual incidence of an event in patients with diabetes.35 Consequently, individuals may increase caloric intake to proactively avoid such an event, and this behavior may result in weight gain. It was demonstrated in the Diabetes Control and Complications Trial that patients who had experienced 1 or more episodes of hypoglycemia gained 6.8 kg in weight, significantly more (2.2 kg) than patients with no severe hypoglycemia.35
Weight gain has also been attributed to the correction of glycosuria. Insulin therapy improves glucose control, so less energy is lost in the urine; hence, if calorie intake is not reduced, patients may experience a gain in weight.36 Carlson and Campbell37 demonstrated glycosuria correction in insulin-induced weight gain in patients with diabetes. A significant gain in body weight (2.6 kg) was found with insulin treatment, of which 2.4 kg was attributed to an increase in fat mass. In addition, daily energy expenditure decreased by 5% with intensive insulin therapy. Hence, insulin therapy causes an increase in body fat as a result of the elimination of glycosuria and a reduction in energy expenditure.
Insulin has also been shown to have fat- and muscle-building (anabolic) effects. The exact mechanism behind this process is not fully understood; however, it has been shown that increases in insulin produce increases in muscle protein and lipogenesis.38,39 Thus, injected insulin may overstimulate muscle and fat cells, increasing tissue density.
Another theory behind weight gain is that insulin may act directly on the central nervous system to influence food intake.40,41 Disruption in these pathways in people with type 2 diabetes could cause weight gain.42,43
A number of strategies have been suggested for weight control in people with diabetes, and multiple approaches are used to achieve optimum results. These strategies include selecting a relevant therapeutic regimen that limits weight gain and appropriately educating the individual with diabetes about lifestyle changes, both of which can help control and maintain body weight.
Many types of insulin are available for treatment of type 2 diabetes. They range from short- and rapid-acting insulins, which are quickly absorbed into the circulation, to longer acting insulins (intermediate- and long-acting insulins), which are absorbed more slowly because of the greater length of time required for the insulin molecules to dilute and diffuse into the bloodstream after injection. Short- and rapid-acting insulins (eg, insulin aspart [NovoRapid®, Novo Nordisk, Bagsvaerd, Denmark], insulin lispro [Humalog®, Eli Lilly, Indianapolis, Ind]) are designed to be injected before or immediately after eating to limit the postmealtime rise in glucose levels. Longer acting insulins (eg, neutral protamine Hagedorn [NPH] insulin, zinc insulin solution, insulin glargine [Lantus®, Sanofi Aventis, Paris, France]) are designed for once-(usually before bedtime) or twice-daily use to provide a low, constant level of insulin. The basal/bolus insulin regimen is commonly used. An individual with diabetes would use basal (longer acting) insulin once or twice daily in the evening and/or morning, with a bolus (rapid-acting) insulin at mealtimes. This allows the individual greater freedom on what can be eaten and when. Many insulins have been compared primarily to examine measures of glycemic control throughout the day and also at mealtimes but also to identify regimens that minimize as far as possible the risk of hypoglycemic episodes. However, the impact of the type of insulin therapy on weight gain should also be accounted for once glycemic control is established. Recently, a new long-acting insulin analog has been developed. In studies involving patients with diabetes, treatment with insulin detemir (Levemir®, Novo Nordisk) resulted in less weight gain than in those patients treated with NPH insulin.44-48 Importantly, efficacy (ie, consistent glycemic control) was not compromised in these studies. As weight gain is a common problem associated with intensive insulin therapy in patients with type 2 diabetes, the introduction of insulin detemir may offer the option of good glycemic control with less weight gain than that seen with other basal insulins. Two novel agents, based on glucoregulatory hormones, have recently become available and may also be appropriate in managing weight in patients with type 2 diabetes. The amylin agonist, pramlintide (Symlin®, Amylin Pharmaceuticals, San Diego, Calif), and the incretin mimetic, exenatide (Byetta®, Amylin Pharmaceuticals), have demonstrated potential in improving glycemic control in patients with diabetes along with the added benefit of weight loss when compared with placebo.49,50
The weight loss medications sibutramine (Meridia®, Knoll Pharmaceuticals, Mount Olive, NJ) and orlistat (Xenical®, Roche, Basel, Switzerland) have been studied as monotherapy and in combination with oral antidiabetic agents in patients with type 2 diabetes.51,52 Although both agents induced significant weight loss and maintained lower weight in 2 studies conducted over 12 months, further studies are required to ensure that this weight loss can be sustained.
Extreme weight problems can be addressed with surgery. Bariatric surgery is considered an acceptable part of treating obesity as part of lifelong behavioral and dietary changes, but it is generally reserved for extreme cases of morbid obesity. Two common forms of bariatric surgery include adjustable gastric banding and a gastric bypass (Roux-en-Y gastric bypass). Both procedures limit food intake by reducing the size of the opening to the stomach (gastric banding) or permanently reducing the size of the stomach, thereby restricting the amount of food that can be comfortably eaten. Bariatric surgery has been linked to a reduced risk or incidence of developing type 2 diabetes.53,54 Used in patients with type 2 diabetes, bariatric surgery has caused major weight loss and even improved glycemic control to the point of remission of the disease in some patients with early-stage diabetes.55,56
The American Diabetes Association recommends that overweight patients with diabetes attain a weight loss of about 5% to 7%, irrespective of initial weight.57 Among overweight people with diabetes, weight loss improves insulin sensitivity and glycemic control,57 whereas even moderate intentional weight loss may be associated with reduced mortality.58 Weight loss also improves lipid profiles and blood pressure,59 as well as mental health and overall quality of life.60,61 However, these benefits are thought to be clinically meaningful only if weight loss is sustained over time.62 Numerous studies have attempted to assess the impact of the implementation of various low-calorie diets on weight loss in patients with diabetes. A recent review of 9 clinical studies63-71 revealed that 6 weeks of a very-low-energy diet (VLED) providing 400 to 800 kcal/d resulted in significant overall decreases in body weight (9.6%), serum cholesterol (9.2%), serum triglycerides (26.7%), systolic blood pressure (8.1%), and diastolic blood pressure (8.6%) in patients with type 2 diabetes.22 VLEDs have been widely used for diabetes management for more than 30 years.72 However, VLEDs require medical supervision, are intensive, and are often expensive.73 Consequently, many physicians now recommend a balanced, calorie-controlled diet providing between 800 and 1200 kcal/d.22 Weight loss diets, with low levels of carbohydrate and high levels of protein, are gaining popularity. A recent small study (n = 12) over 8 weeks compared a high-protein diet (40% carbohydrate, 30% protein, 30% fat) to a high-carbohydrate diet (55% carbohydrate, 15% protein, 30% fat) in patients with type 2 diabetes.74 Patients in both groups lost weight (–2.2 and –2.5 kg), but mean hemoglobin A1C and fasting plasma glucose levels decreased significantly (8.2% to 6.9% and 8.8 to 7.2 mmol/L, respectively, P < .05) only in the patients on the high-carbohydrate diet. Regular exercise may promote long-term weight loss, provided that patients adhere strictly to the regimen.75 Exercise can lower the blood sugar, improve the body's ability to use glucose, and decrease the amount of insulin needed.76 However, as those with type 2 diabetes generally have a lower level of fitness than nondiabetic individuals do, exercise intensity should be at a comfortable level in the initial periods of training and should progress cautiously as tolerance for activity improves.77 Lifestyle changes such as those outlined above can be discussed with patients in group therapy sessions. Regular meetings with patients, possibly involving psychologists and dietitians, can help reinforce and encourage patients to continue with their diet and exercise programs. Psychologists can help in this setting by introducing behavioral therapy aimed at improving a patient's body image and attitude toward eating. Self-management is an important part of caring in type 2 diabetes. Diabetes educators including nurses, dietitians, exercise physiologists, and behavior specialists can help to address weight gain in patients by identifying areas for improvement in self-management. Comprehensive assessment of the barriers to weight loss can recognize areas in which the patient may need encouragement and help. For example, following dietary recommendations may be particularly burdensome for a patient with type 2 diabetes because of cost, a perceived decrease in quality of life, limited portions, dislike of particular foods, or restrictions over holidays and special events.78 Consequently, awareness of these barriers can be used to tailor the educational material received from educators as well as the way the information is delivered to patients; incorporating information about these barriers can help to support the patient. Ongoing, tailored, self-management interventions can be integrated into routine care and may prove useful in the continuing education of the patient. For example, a brief self-management program aimed at helping patients to adopt low-fat eating patterns and increasing physical activity levels via motivational interviews and follow-up telephone contact has reported some success in weight maintenance.79 A similar study looking at improving selfcare behavior has reported weight loss and improvements in healthy eating and glycemic control.80 Nurses and other members of the patient's health care team can also encourage and educate the patient about diabetes therapy. It is possible that patients see the introduction of insulin as a personal failure in controlling their disease81; patients need to have these concerns addressed and be reassured that taking insulin is a positive step in the management of their treatment and will not adversely affect their quality of life82 and that any associated weight gain can be addressed and managed through a variety of options.83
Insulin treatment has been shown to vastly improve the prognosis in patients with type 2 diabetes. However, weight gain is an unfortunate problem often associated with insulin treatment. Improvements in the quality of diet and physical health should provide the core component of weight management in patients with type 2 diabetes.84 Reductions in dietary fat can improve health and assist in weight loss. Restrictive dieting has been shown to significantly decrease body weight; however, such diets are often expensive and difficult to manage.73 The introduction of a new type of long-acting basal insulin, insulin detemir, may herald an opportunity to conduct intensive treatment without the fear of weight gain. Novel medications can also improve metabolic control without the burden of weight gain. Whatever the course of action taken in patients with type 2 diabetes, weight management must always remain a priority as the great benefits of insulin treatment may be undermined.
Thank you to the Why Wait? team at the Joslin Clinic in Boston for their commitment to building personal therapeutic relationships and facilitating the achievement of amazing goals: Osama Hamdy, MD, PhD, program director, diabetes and weight management; Ann Goebel-Fabbri, PhD, psychologist; Gillian Grant, MS, RD, CDE, dietitian; Jackie Shahar, MS, LATC, exercise physiologist; Roberta Capelson, MS, ANP, nurse practitioner; Joan Beaton, program coordinator; Martin Abrahamson, MD, medical director, Joslin Diabetes Center. Most important, thank you to the patients who participate in the Why Wait? program.
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Abstract
Evaluating Obesity and Weight...