Weight Loss as a Cure for Type 2 Diabetes
Weight Loss as a Cure for Type 2 Diabetes
Although individuals with obesity and Type 2 diabetes are insulin resistant, pancreatic β-cell failure is the core defect that distinguishes individuals who eventually develop diabetes. This process is known to occur well before the onset of hyperglycemia. Although clinical trial data support the effectiveness of intensive lifestyle modification in delaying the onset of diabetes in obese subjects, less is known about the effects of, and mechanisms underlying, bariatric surgery, particularly gastric bypass surgery, on diabetes. The paper under evaluation clarifies the role of both lifestyle intervention and gastric bypass surgery on pancreatic β-cell function and raises questions regarding the role of weight loss versus incretin-related mechanisms on recovery of β-cell failure.
The current pandemic of Type 2 diabetes and obesity has created an urgent need to identify effective therapeutic interventions targeting both of these chronic debilitating conditions. Obesity and diabetes are closely interrelated (see Figure 1) in that risk factors such as physical inactivity and poor diet lead to weight gain and precipitate insulin resistance in important insulinsensitive tissues, particularly skeletal muscle, 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 TNF-α and IL-6, and reduced secretion of adiponectin. These factors have been shown to be part of the underlying mechanisms of glucose intolerance and contribute to reduced skeletal muscle glucose disposal and increased hepatic glucose output. Although insulin resistance is common in obese patients, diabetes is not always present because the pancreas augments insulin production as a means to offset the severity of impaired insulin action. The transition from a mild state of insulin resistance to Type 2 diabetes is heralded by progressive pancreatic β-cell dysfunction and eventual failure to secrete adequate amounts of insulin; all of this occurs well before the inception of diabetes. In obese individuals with a familial tendency for Type 2 diabetes, impaired insulin secretion is documented early on in the spectrum of glucose tolerance. In certain high-risk populations, up to 80% of pancreatic β-cell failure is observed to occur during the fasting state and manifests in a condition now known as impaired fasting glucose. According to Defronzo, as fasting hyperglycemia develops, insulin secretion decreases progressively and in patients with fasting glucose levels of 180–200 mg/dl, there is an absolute deficiency of insulin. Some major nonheritable factors implicated in β-cell failure, particularly in obesity, include elevated free fatty acids and inflammatory cytokines, termed as 'lipotoxicity', and incretin deficiency and/or resistance.
(Enlarge Image)
Figure 1.
Pathophysiology of Type 2 diabetes in the setting of obesity. Chronic caloric surplus and physical inactivity lead to obesity and insulin resistance. β-cell failure is required in this setting to drive the transition from obesity/insulin resistance to Type 2 diabetes. Both Roux-en-Y gastric bypass surgery and diet/exercise contribute to β-cell recovery through weight loss, restoration of incretin function and improvement of insulin sensitivity. Evidently, the magnitude of these effects (represented by the '+' symbol) is far greater following bariatric surgery than diet/exercise interventions.
IGT: Impaired glucose tolerance; NGT: Normal glucose tolerance; RYGB: Roux-en-Y gastric bypass.
Modest weight loss of 5–10% bodyweight is known to improve diabetes by reducing insulin resistance in obese individuals. In clinical trials, caloric restriction, exercise and weight loss have been shown to prevent and reduce diabetes in obese individuals, in part by attenuating insulin resistance and subsequent hyperinsulinemia, thereby preserving β-cell function. It has also been shown that weight loss surgery, particularly gastric bypass surgery, has a profound effect on metabolism and can induce remission of Type 2 diabetes defined by normal glycemic control without the need for diabetic medications. The fundamental questions brought forth regarding these latter observations include: Can weight loss effectively reverse pancreatic β-cell dysfunction? If so, which specific therapeutic weight-loss modality (i.e., lifestyle, pharmacotherapy or surgery) produces the most effective and sustained reversal of pancreatic β-cell dysfunction in individuals with diabetes or a predisposition towards diabetes?
Abstract and Introduction
Abstract
Although individuals with obesity and Type 2 diabetes are insulin resistant, pancreatic β-cell failure is the core defect that distinguishes individuals who eventually develop diabetes. This process is known to occur well before the onset of hyperglycemia. Although clinical trial data support the effectiveness of intensive lifestyle modification in delaying the onset of diabetes in obese subjects, less is known about the effects of, and mechanisms underlying, bariatric surgery, particularly gastric bypass surgery, on diabetes. The paper under evaluation clarifies the role of both lifestyle intervention and gastric bypass surgery on pancreatic β-cell function and raises questions regarding the role of weight loss versus incretin-related mechanisms on recovery of β-cell failure.
Introduction
The current pandemic of Type 2 diabetes and obesity has created an urgent need to identify effective therapeutic interventions targeting both of these chronic debilitating conditions. Obesity and diabetes are closely interrelated (see Figure 1) in that risk factors such as physical inactivity and poor diet lead to weight gain and precipitate insulin resistance in important insulinsensitive tissues, particularly skeletal muscle, 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 TNF-α and IL-6, and reduced secretion of adiponectin. These factors have been shown to be part of the underlying mechanisms of glucose intolerance and contribute to reduced skeletal muscle glucose disposal and increased hepatic glucose output. Although insulin resistance is common in obese patients, diabetes is not always present because the pancreas augments insulin production as a means to offset the severity of impaired insulin action. The transition from a mild state of insulin resistance to Type 2 diabetes is heralded by progressive pancreatic β-cell dysfunction and eventual failure to secrete adequate amounts of insulin; all of this occurs well before the inception of diabetes. In obese individuals with a familial tendency for Type 2 diabetes, impaired insulin secretion is documented early on in the spectrum of glucose tolerance. In certain high-risk populations, up to 80% of pancreatic β-cell failure is observed to occur during the fasting state and manifests in a condition now known as impaired fasting glucose. According to Defronzo, as fasting hyperglycemia develops, insulin secretion decreases progressively and in patients with fasting glucose levels of 180–200 mg/dl, there is an absolute deficiency of insulin. Some major nonheritable factors implicated in β-cell failure, particularly in obesity, include elevated free fatty acids and inflammatory cytokines, termed as 'lipotoxicity', and incretin deficiency and/or resistance.
(Enlarge Image)
Figure 1.
Pathophysiology of Type 2 diabetes in the setting of obesity. Chronic caloric surplus and physical inactivity lead to obesity and insulin resistance. β-cell failure is required in this setting to drive the transition from obesity/insulin resistance to Type 2 diabetes. Both Roux-en-Y gastric bypass surgery and diet/exercise contribute to β-cell recovery through weight loss, restoration of incretin function and improvement of insulin sensitivity. Evidently, the magnitude of these effects (represented by the '+' symbol) is far greater following bariatric surgery than diet/exercise interventions.
IGT: Impaired glucose tolerance; NGT: Normal glucose tolerance; RYGB: Roux-en-Y gastric bypass.
Modest weight loss of 5–10% bodyweight is known to improve diabetes by reducing insulin resistance in obese individuals. In clinical trials, caloric restriction, exercise and weight loss have been shown to prevent and reduce diabetes in obese individuals, in part by attenuating insulin resistance and subsequent hyperinsulinemia, thereby preserving β-cell function. It has also been shown that weight loss surgery, particularly gastric bypass surgery, has a profound effect on metabolism and can induce remission of Type 2 diabetes defined by normal glycemic control without the need for diabetic medications. The fundamental questions brought forth regarding these latter observations include: Can weight loss effectively reverse pancreatic β-cell dysfunction? If so, which specific therapeutic weight-loss modality (i.e., lifestyle, pharmacotherapy or surgery) produces the most effective and sustained reversal of pancreatic β-cell dysfunction in individuals with diabetes or a predisposition towards diabetes?
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