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Abstract

Increasing overweight and obesity are major risk factors for the development of type 2 diabetes. The risk is higher when the weight gain occurs during adulthood. In fact, evidence shows that body mass index (BMI) is directly and continuously related to the risk of type 2 diabetes. Individuals with upper body obesity are at high risk for hyperinsulinemia, insulin resistance, and type 2 diabetes. According to the US Centers for Disease Control and Prevention, rates of type 2 diabetes have tripled in the past 30 years. This is caused largely by the rapid rise in the rate of obesity, a major risk factor for developing type 2 diabetes and pre-diabetes. Over the last decade, there has been a rapid escalation in the prevalence of obesity, one that parallels the equally rapid increase in type 2 diabetes. The development of type 2 diabetes can be delayed or sometimes prevented in individuals with obesity who are able to lose weight. In type 2 diabetes, weight loss improves glycemic control and cardiovascular disease risk factors. Strategies to decrease the risk of type 2 diabetes include behavior therapies in combination with healthy lifestyle changes, optimizing medication for weight neutral effect, anti-obesity medication, and weight loss surgeries.

Corresponding Author(s)

Adarsh K. Gupta, DO, MS, FACOFP, Director, Center for Medical Weight Loss and Metabolic Control, UMDNJ-SOM, 42 East Laurel Rd, Suite 2100, Stratford, NJ 08084.

E-mail address: guptaad@umdnj.edu

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Increasing overweight and obesity are major risk factors for the development of type 2 diabetes.1-3A large body of evidence exists that attests to the relationship between excess weight and an increased risk of development of type 2diabetes.4,5The risk increases with the degree of excess weight, increasing 3-fold with a body mass index (BMI) of 25.0-29.9 kg/m2and 20-fold with a BMI30 kg/m2, which is the “obese” category.6The risk is also higher when the weight gain occurs during adulthood.7,8 Evidence shows that BMI is directly and continuously related to the risk of type 2 diabetes.9 Individuals with upper body obesity are at high risk for hyperinsulinemia, insulin resistance, and type2 diabetes.

According to the US Centers for Disease Control and Prevention, rates of type 2 diabetes have tripled in the past30 years.11This is caused largely by the rapid rise in the rate of obesity, a major risk factor for developing type 2 diabetes and pre-diabetes. Over the last decade, there has been a rapid escalation in the prevalence of obesity, one that parallels the equally rapid increase in type 2 diabetes. In 2009, all states continued to have a high prevalence of obesity among adults, although the prevalence varied geographically. No state met the Healthy People 2010 target of 15%,and the number of states with obesity prevalence of30% increased from none in 2000 to nine in 2009.

The current pandemic of type 2 diabetes and obesity has created an urgent need to identify effective therapeutic in- terventions targeting both of these chronic debilitating conditions. Obesity and diabetes are closely interrelated in that risk factors such as physical inactivity and poor diet lead to weight gain and precipitate insulin resistance in important insulin-sensitive tissues, particularly in skeletal muscle, the liver, and adipose tissue. It is known that obese and insulin- resistant diabetic patients have a positive energy balance, high fat and high carbohydrate intake, increased abdominal adipose tissue, elevated free fatty acids, increased secretory products of adipocytes mediating inflammation including tumor necrosis factor (TNF)-a and interleukin (IL)-6, and reduced secretion of adiponectin.13

Given the strong relationship between type 2 diabetes and obesity, prevention of weight gain should be the cardi- nal focus in treatment strategies. In type 2 diabetes, weight loss improves glycemic control and cardiovascular disease risk factors. Strategies to decrease the risk of type 2 diabetes include behavior therapies in combination with lifestyle changes, weight loss medications and weight loss surgeries.


‌Adipocytes and type 2 diabetes

Adipocytes are not simply storage reservoirs of fat but they are active endocrine organs that play multiple roles in body.Adipose tissue is currently known to secrete a large number of proteins termed adipokines that act in an autocrine, paracrine, or endocrine fashion to control various metabolic functions.16 These adipokines have been linked to a state of inflammation and the impairment of insulin sensitivity.When compared with lean individuals, adipose tissue in obese individuals shows higher expression of pro inflammatory proteins, including TNF-and IL-6. Macrophage numbers in adipose tissue also increase with obesity. Macro-phage accumulation and the subsequent local inflammation are believed to result in numerous metabolic dysfunctions that accompany obesity, including systemic inflammation and atherosclerosis.17Visceral fat secretes more cytokines than subcutaneous adipose tissue.18Macrophages with invisceral adipose tissue are known to express and release cytokines. These cytokines reach the liver though the portalcirculation, where they can stimulate hepatic inflammation,19 thereby inducing a chronic systemic inflammatory response. A reduction of fat mass that occurs with weightloss results in a reduction of lipid oxidation and an enhancement of glucose metabolism.20

‌Weight management for diabetes

Counseling patients on lifestyle modifications should be the first line of defense. There is also a great need for safe and efficacious drugs to treat obesity. The only drug currently approved for long-term obesity management— orlistat— provides only modest weight-loss benefits. Very-low-calo- rie diets can be effective if supervised by a physician and followed correctly but their duration is inevitably short- term. The bariatric surgical procedure of gastric banding becomes the next option to consider. It should be preferred ahead of other bariatric procedures because it is minimally invasive, has a better safety profile than other procedures, and is potentially reversible.


‌Weight loss medications

Currently available medications to treat obesity are lim- ited in number and efficacy. Most of those drugs work in the central nervous system and in the gastrointestinal tract. The effects of these medications on weight loss are modest. However, weight loss medications along with lifestyle mod-

‌Drugs approved by the US Food and Drug Administration for the treatment of obesity

‌Orlistat

using orlistat, it is recommended that they take a multivita- min daily with emphasis of fat-soluble vitamins (A, D, E, K) because they may not be adequately absorbed from diet because of this medication.


‌Rimonabant

Rimonabant, a selective cannabinoid-1 receptor blocker, has been approved in many European countries as an anti- obesity drug. However, in 2007, the FDA denied approval in the US because of concern over “increased frequencies of psychiatric adverse effects,” including suicide and sei- zures.32 In a study of more than 1000 patients on metformin or sulfonylurea monotherapy, with type 2 diabetes and BMI ranging from 27-40 kg/m2 and HbA1c ranging from 6.5- 10%, patients were given a hypocaloric diet and advice for increased physical activity. They were then randomized to receive a placebo or a 5- or 20-mg/d dose of rimonabant for one year. Weight loss was significantly greater after one year in the two rimonabant groups vs. the placebo group

(-2.3 kg for the 5-mg/d group and -5.3 kg for the 20-mg/d group vs. -1.4 kg for the placebo). An improvement in HbA1c was also observed in both treatment groups (-0.1% for the 5-mg/d group, -0.6% for the 20-mg group vs 0.1% for the placebo group).33 The incidence of adverse events

that led to discontinuation of the study was slightly greater in the high-dose rimonabant group, mainly because of de- pressed mood disorders, nausea, and dizziness.


‌New drugs on the horizon

Several new pharmacologic agents have been examined in late-stage clinical trials. They include locaserine, a nal- trexone-bupropion combination, and a phentermine-topira- mate combination. Each of these agents has been demon- strated to induce significant weight loss in patients who are overweight or have obesity.


‌Lorcaserin. Lorcaserin is a selective agonist of the 5-HT2c serotonin receptor. At clinically effective doses, lorcaserin does not activate the 5-HT2B receptor, which appears to be the receptor primarily responsible for the cardiac valvular disease associated with fenfluramine. Recent large, phase 3 trials of lorcaserin revealed no valvulopathy resulting from the use of this agent. These trials demonstrated an average weight loss of 5.8% of the subject’s body mass, as opposed to 2.5% for those taking placebo.34 However, the FDA panel voted against approving this drug in September 2010, stating that the benefits were too limited in the face of the risks associated with taking the drug. At the time of this writing, Arena pharmaceutical is still in discussion with the FDA for approval of this drug, and we should soon know the outcome.


‌Naltrexone-bupropion (Contrave). Naltrexone is an opioid receptor antagonist that has been used as an adjunctive therapy for the treatment of substance abuse and addic-


‌Phentermine-topiramate (Qnexa). Several clinicians have noted weight loss effects with topiramate. It was also noted that the combination of phentermine and topiramate can generate substantial weight loss in at least a subset of patients who exhibit little weight loss when treated with phentermine alone. This observation led to the development of fixed-dose combinations of phentermine and topiramate. The phase III EQUATE trial evaluated Qnexa vs. placebo in 756 obese subjects over 28 weeks. Patients taking full-dose and mid-dose Qnexa achieved an average weight loss of 9.2% and 8.5% respectively, compared with 1.7% reported for the placebo group.38 This drug recently received 20-2 votes by an FDA panel. The FDA is expected to decide whether to approve Qnexa by April 17, 2012.


‌Selected diabetic medications (metformin, exenatide, pramlintide)

weight than those taking placebo (p < 0.05), and those treated with 2.4 or 3.0 mg of liraglutide lost more weight than those taking orlistat (p < 0.05).41 The protease-resis- tant GLP-1 congener exenatide has been approved for treat-

ing type 2 diabetes. In clinical diabetes trials, it also caused modest weight loss (3%). Recently, an extended-release formulation of exenatide with the brand name of Bydureon (Amylin Pharmaceuticals, San Diego, CA) has also been approved by the FDA. This is an injectable form that is

given once a week. Amylin, a peptide co-secreted with insulin from pancreatic � cells, inhibits gastric emptying and glucagon secretion and promotes satiety. Pramlintide is an injectable synthetic analogue of the hormone amylin that is approved as an adjunct therapy in patients with type 1 and type 2 diabetes mellitus who fail to achieve optimal glucose control despite insulin therapy. In a one-year study of pram- lintide in patients with type 2 diabetes, patients lost 0.4 kg compared with a 0.8-kg weight gain in the placebo group.42


‌Very-low-calorie diet program

Very-low-calorie diets (VLCDs) are defined as diets lim- iting energy intake to 1.88-3.35 MJ (450-800 kcal) per day while providing at least 50 g of high-quality protein and amino acids, essential fatty acids, and daily requirements of trace elements, vitamins, and minerals. They are recom- mended only in the obese (BMI 30 kg/m2) or in individuals

with BMIs >27 kg/m2 plus one or more comorbidities. After initiation of a VLCD, hyperglycemia decreases within


‌Weight loss surgery

Surgical options are appropriate in patients with high BMIs (>35 kg/m2) and type 2 diabetes who have not been able to lose significant amounts of weight through lifestyle interventions alone or lifestyle interventions combined with weight loss medications. In obese patients who also have

Weight loss surgeries can be classified as two major types: (1) Gastric restrictive procedures and (2) intestinal bypass procedures. The classification was initially based on the presumed mechanism of weight loss.

Gastric restrictive procedures (laparoscopic adjustable gastric banding, sleeve gastrectomy, vertical gastroplasty) limit gastric volume and, hence, restrict the intake of calo- ries by inducing satiety. After the procedure, patients lose approximately 10-20% of their total body weight. Further- more, multiple studies, including a randomized, controlled this trial, all patients had diabetes of short duration (<2 years).

Intestinal bypass procedures (Roux-en-Y gastric bypass, biliopancreatic diversion) also restrict caloric intake, similar to gastric banding and vertical gastroplasty. Because the small intestine is shortened in intestinal bypass procedures, there is an added component of malabsorption of fat and nutrients. After the procedure, more patients experience remission of type 2 diabetes (82-99%) than after gastric restrictive operations, even patients with longer duration of disease, including those treated with insulin.29


‌Conclusions

Type 2 diabetes is a progressive disease that can become more difficult to treat with time. Obesity leads to increased inflammation and insulin resistance. Weight loss can help reduce the insulin resistance and improve hyperglycemia. Health care providers should evaluate for obesity and weight gain in diabetic patients and offer lifestyle modifi- cation treatment, including behavior modification, diet, and physical activity therapies. When these treatments are not enough, weight loss medication and/or bariatric surgery therapies should be offered in conjunction with lifestyle modification treatment.


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