Reinventing Type 2 Diabetes: Title and subTitle BreakPathogenesis, Treatment, and Prevention

The conventional glucocentric perspective of type 2 diabetes views hyperglycemia as a primary disease caused by an etiologically uncertain combination of obesity-associated insulin resistance and beta cell loss (a disease of glucose metabolism to be treated with antihyperglycemic agents, including high-dose insulin, if necessary). By contrast, the novel lipocentric view depicts the hyperglycemia of type 2 diabetes, and the underlying insulin resistance and beta cell loss, as being secondary to the metabolic trauma caused by ectopic lipid deposition or lipotoxicity.¹ If this is in fact the case, hyperglycemia should be corrected by eliminating the lipid overload. The study by Dixon et al² provides support for this lipocentric hypothesis, by demonstrating that weight loss that follows gastric banding is accompanied by remission of diabetes in 73% of obese patients with type 2 diabetes. This finding supports 45 years of biochemical, physiological, and clinical research pointing to lipid overload as the underlying cause of this disease and of the other coexisting components of the metabolic syndrome.

During the past half century, US individuals have been exposed to 2 historically unprecedented changes in their caloric environment that would predispose to lipid overload. First, meal preparation was increasingly outsourced from the family kitchen to commercial processors and purveyors of lipid-rich, calorie-dense foods, resulting in a 168-kcal/d and a 335-kcal/d increase in the caloric intake of men and women, respectively, during the past 30 years.³ Second, during the same period physical activities that had always been a part of normal life have been substantially decreased or eliminated by a variety of immobilizing technologies, causing a substantial decrease in daily caloric expenditure.⁴ Not surprisingly, this caloric surplus has dramatically altered the body habitus of most US individuals, more than two-thirds of whom are now overweight or obese.⁵

Not long after the start of this obesity epidemic, Yalow and Berson⁶ reported the development of the radioimmunoassay for insulin, an achievement that was to earn a Nobel Prize. This new technology led to the discovery that overweight individuals with normal glucose levels have higher insulin levels than normal-weight individuals.⁷ The coexistence of hyperinsulinemia and normoglycemia implied resistance to the action of insulin. This interpretation was soon confirmed with the development of techniques for precise measurement of insulin action on glucose metabolism,⁸ and along with other studies demonstrated a relationship between obesity and insulin resistance.^{9 - 10} However, the mechanism of this relationship and its clinical consequences continued to be a matter of some controversy, despite a relative consensus that insulin resistance is related to overt type 2 diabetes and the other morbidities of the metabolic syndrome.¹¹

During the same decade, the concept of a relationship between glucose and lipid metabolism emerged. In 1963, Randle et al¹² proposed a “glucose-fatty acid cycle,” which provided a plausible biochemical explanation for lipid-induced impairment of glucose metabolism that could cause insulin resistance. In 1992, McGarry¹³ advanced the position that abnormal metabolism of lipids, not glucose, might be the primary metabolic defect in type 2 diabetes. Indeed, there is now evidence that in muscle, fatty acids inhibit insulin-mediated glucose uptake by interfering with the translocation of the glucose transporter GLUT-4 to the plasma membrane, thus effectively blocking glucose uptake by myocytes; whereas, in liver, fatty acids inhibit insulin-mediated suppression of glycogenolysis and gluconeogenesis.¹⁴ New insights into the mechanistic links between lipid metabolism and insulin resistance have been provided by the use of isotopes and magnetic resonance spectroscopy.¹⁵ But whatever the precise molecular pathways to insulin resistance, there seems to be broad consensus that ectopic accumulation of unoxidized fatty acids is a major factor. In 1994, Lee et al¹⁶ demonstrated that ectopic lipids accumulate in pancreatic islets in parallel with other tissues and can cause the subtotal lipotoxic destruction of beta cells that precipitates the hyperglycemia, thereby providing the final evidence for the lipocentric theory of type 2 diabetes.

If surplus lipids are in fact the link between obesity and insulin resistance, the phrase “insulin resistance of obesity” becomes oxymoronic, in as much as the presence of obesity constitutes evidence for robust activity of a major insulin-mediated process, lipogenesis. Neither obesity nor ectopic lipid overload with which it is so commonly associated could occur were there resistance to insulin-mediated lipogenesis. Resistance to insulin action on glucose metabolism but sensitivity to insulin action on lipogenesis is a paradox. A molecular explanation for the paradox was reported in 2000 when insulin was shown to down-regulate insulin receptor substrate 2, while stimulating the production of sterol response element binding protein 1c (SREBP-1c), a transcription factor that stimulates lipogenesis.¹⁷ This dichotomous relationship explains how the liver continues to synthesize fatty acids while resisting insulin-mediated suppression of hepatic glucose production.

Based on the epidemiological, clinical, metabolic, and molecular information now available, the following teleologically plausible pathway emerges, with increased caloric balance as the primary perturbation: (1) caloric surplus → (2) hyperinsulinemia → (3) increased expression of the lipogenic transcription factor SREBP-1c → (4) increased lipogenesis → (5) increased adiposity → (6) ectopic lipid deposition → (7) insulin resistance→ (8) beta cell lipotoxicity→ (9) hyperglycemia. Not only is this scheme historically and epidemiologically congruent with the change in the caloric environment, but it fits physiologically with the known actions of overnutrition on insulin secretion and the known actions of insulin on the disposition of unused calories—initially as fat in adipocytes—but ultimately as ectopic fat in nonadipocytes, such as myocytes and hepatocytes. If this formulation is correct, resistance to insulin-mediated uptake of glucose in tissues associated with increasing ectopic lipid deposition may serve as a compensatory adaptation designed to limit further lipid accumulation by keeping lipogenic substrate out of liver cells, even at the cost of an abnormal glucose tolerance test.¹⁸

This lipocentric conceptual revision may have at least 2 important clinical implications. First, there has long been evidence that relatively modest weight loss by caloric restriction, by exercise, or both can reduce insulin resistance and hyperglycemia, even if it fails to achieve its desired cosmetic goal.¹⁹ In other words, overweight individuals should restrict calories to prevent disease, whether or not optimal weight loss is achieved.

Second, the lipocentric concept raises questions as to the preferred therapy for obese patients with poorly controlled, insulin-resistant type 2 diabetes. The availability of U500 insulin now makes it easier to administer the doses of insulin necessary to overpower insulin resistance. But is it rational to overpower resistance to insulin without eliminating the caloric excess that created the abnormalities? Or might the superimposition of exogenous hyperinsulinemia on preexisting endogenous hyperinsulinemia worsen the ectopic lipid overload by providing yet more substrate for lipogenesis from the continuing surplus of calories? If so, intensive insulin therapy would be relatively contraindicated. For instance, the National Institutes of Health announced on February 8, 2008, that the National Heart, Lung, and Blood Institute has halted a clinical trial of aggressive lowering of blood glucose levels in patients with high-risk type 2 diabetes because of an increase in deaths from myocardial infarction or stroke.²⁰ In this study, a part of the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, blood glucose levels were maintained as close to normal as possible and some patients reportedly received as many as 5 insulin injections per day. The unfortunate outcome suggests that overpowering the insulin resistance may be harmful, quite possibly because doing so forces lipogenesis and promotes ectopic deposition of lipids.

This should in no way be construed as minimizing the importance of treating the hyperglycemia. It merely advocates a strategy that would eliminate hyperglycemia without amplifying the underlying abnormality, the ectopic lipid overload. The most rational therapy would be one that eliminates the caloric surplus and thus reduces the hyperinsulinemia and the lipogenesis. This will slowly decrease lipogenesis and ectopic lipid deposition, and the hyperglycemia will gradually decline. If hyperglycemia fails to decline, anti-diabetic drugs that reduce food intake, that reduce ectopic lipids, or that do both can be added.²¹ Bariatric surgery may provide perhaps the most certain way to reverse the chronic caloric surplus and the lipid overload.³ If hyperglycemia persists despite aggressive diet restriction and weight loss, insulin therapy will be required as a last resort. The preferred strategy to correct hyperglycemia is to eliminate its proximal cause, caloric surplus. This will gradually reduce the diet-driven hyperinsulinemia and excessive lipogenesis that is responsible for the abnormal glucose metabolism.