Type 2 diabetes is a multifactorial metabolic disease.1 Obesity, elevated levels of lipids and insulin in the blood, and insulin resistance all accompany the elevated blood glucose that defines diabetes. (Diabetes is defined as fasting blood glucose concentrations above 7 millimolar (mM), or above 11 mM two hours after ingestion of 7five grams of glucose.) Yet while researchers have actually made much progress in understanding these components of the metabolic dysfunction, one major question remains: Exactly what serves as the primary driver of disease?
Lifestyle selections characterized by inactivity have actually been postulated as one feasible cause. Researchers have actually likewise pointed the finger at nutrition, postulating that poor meals selections can easily contribute to metabolic disease. However, there is thus far weak support for these hypotheses. Changing to a healthy and balanced diet typically does not result in considerable fat burning or the resolution of metabolic dysfunction, and it is rare to reverse obesity or diabetes through increased exercise. Furthermore, there does not appear to be a durable partnership between body-mass index (BMI) and activity level, though exercise clearly has actually lots of various other health benefits.
With such macroscale factors unable to explain most cases of obesity and diabetes, scientists have actually looked to molecular mechanisms for answers. There are at least 40 genetic mutations known to be associated Along with type 2 diabetes. These genes tend to be involved in the function of pancreatic β cells, which secrete insulin in response to elevated levels of the three types of cellular fuel: sugar, fat, and protein. In healthy and balanced young adults, circulating glucose concentrations above concerning five millimolar (mM) trigger release of insulin from β cells. Once fatty acids or amino acids are likewise elevated, the glucose-triggered insulin release is greater. Insulin facilitates the uptake of these molecules by the body’s tissues, leading to a decrease in their levels in the blood.
To date, most researchers have actually focused on insulin resistance, or the failure of insulin-sensitive cells in muscle, fat, liver, and various other tissues to respond to the hormone, as the driver of dysfunction in this feedback cycle, assuming the various other metabolic changes observed in type 2 diabetics to be symptoms of such flawed insulin signaling. However, some insulin-resistant people are capable of maintaining normal blood glucose levels, albeit by making higher-than-normal levels of insulin. Moreover, if insulin resistance leads to metabolic dysfunction, then increasing levels of insulin must restore metabolic homeostasis. Yet treating insulin-resistant patients Along with drugs such as sulfonylureas or injected insulin is actually followed by greater metabolic imbalance.
In light of these findings, it’s time to start considering Exactly what various other metabolic correlates of diabetes could be driving factors. Elevated levels of lipids and insulin—both of which are seen prior to and at the onset of type 2 diabetes—are top candidates. Hyperlipidemia, the state of persistently Higher circulating levels of lipids called triglycerides, stimulates insulin secretion, leading to elevated insulin levels, or hyperinsulinemia. Inducing hyperinsulinemia in animal models can easily lead to insulin resistance and obesity.2
Prevention and treatment of type 2 diabetes depends on correctly determining the cause of metabolic failure. In fact, two available drugs (metformin and thiazolidinediones) produced to treat insulin resistance may actually job by lowering lipids. In combination Along with mounting evidence from our group and others that lowering circulating levels of insulin and lipids can easily reverse metabolic dysfunction in rodent models, researchers ought to now think of feasible triggers various other compared to insulin resistance and try targeting these factors for brand-new diabetes treatments.
Exploring hyperlipidemia and hyperinsulinemia
Obesity is accompanied by an uptick in circulating triglycerides and free fatty acids that come from increased adipose tissue mass. Triglycerides stored in fat cells (adipocytes) are broken down in to fatty acids, and these lipids can easily enter β cells, where they generate signals to increase insulin secretion, resulting in elevated blood insulin levels. This signaling cascade is typically initiated inside the b cell by the attachment of coenzyme A (CoA) to the fatty acids, forming long-chain acyl-CoA. Acyl-CoA itself is a well-established and potent signaling molecule and is the precursor of various other necessary signaling molecules such as diglycerides and monoglycerides. In pancreatic β cells, acyl-CoA has actually been shown to directly stimulate insulin exocytosis, adjustment membrane ion channel activity, and influence Ca2+ handling.3 (See illustration below.)
To explore the importance of long-chain acyl-CoA in the development of diabetes, researchers studying rodent models have actually replaced dietary long-chain triglycerides Along with medium-chain triglycerides, which are rapidly oxidized in the mitochondria and thus do not generate cytoplasmic acyl-CoAs to stimulate insulin release. Once a pair of researchers at McGill University in Quebec tried this treatment in mice, the animals had lower fasting insulin secretion and restored ability to respond to stimulatory glucose. They endured no weight gain or increased fat mass, and they did not suffer from impaired glucose tolerance, which typically accompanies a high-fat diet. In addition, mice that consumed medium-chain triglycerides were satiated a lot more quickly compared to animals fed long-chain fats, reducing their overall meals consumption.4
Stimulating weight loss to decrease lipid stores can easily likewise reduce circulating lipids and cytoplasmic long-chain acyl-CoA. Activating the transcription factor PPARα enhances expression of enzymes called for for long-chain acyl CoA oxidation. In rodent models of high-fat diet–induced obesity, treatment Along with the PPARα agonist fenofibrate effectively stimulated fat burning. In overweight mice, fenofibrate reasonable circulating levels of fatty acids and triglycerides while reversing hyperinsulinemia and hyperglycemia; in rats, fenofibrate likewise increased metabolic rate.5
These findings point to hyperlipidemia as a driving force in the development of metabolic dysfunction: by reducing levels of circulating lipids, researchers have actually successfully stunted the development of diabetes in animal models. Yet there is likewise evidence that hyperinsulinemia is the initiating defect that leads to obesity, hyperlipidemia, and insulin resistance. In 2000, Christian Weyer, then at the Clinical Diabetes and nourishment Section at the National Institutes of Health, and colleagues found that hyperinsulinemia precedes and predicts the development of diabetes in Pima Indians.6 Their findings fit Along with several previous studies of people in various other ethnic groups prone to obesity, such as Mexican Americans and Nauruans, that likewise concluded hyperinsulinemia predicts diabetes.7,8,9,10
By reducing levels of circulating lipids, researchers have actually successfully stunted the development of diabetes in animal models.
Other evidence for hyperinsulinemia as a cause of diabetes comes from gastric bypass surgery, an effective treatment for some patients Along with type 2 diabetes. In 2011, Walter Pories and G. Lynis Dohm at East Carolina University published a review documenting that, following surgery, patients endured a decrease in fasting insulin levels, along Along with decreases in blood glucose and resolution of diabetes within a week—well prior to patients showed considerable weight loss.11 Inhibiting insulin secretion in rats can easily Avoid the development of the metabolic abnormalities induced by a high-sucrose diet;12 in vitro, curbing insulin secretion can easily preserve human islets from deteriorating and becoming ineligible for islet transplantation.13
As for how hyperinsulinemia might cause metabolic problems, it has actually been known since the 1970s that insulin can easily downregulate its own receptor. Once insulin binds its receptor, the cell internalizes the complex, digesting the attached insulin and recycling most of the receptors to the membrane surface. At chronically Higher insulin levels, such recycling can easily exhaust the receptors, such that there are few on the cell surface to respond to further enhances in insulin. Moreover, my group recently showed that hypersecretion of insulin can easily deplete the insulin reserves of β cells in vitro. This leaves the cells unable to fully respond to a surge in glucose—a precursor to β-cell failure. In this case, we exposed the β cells to excess glucose and fat to cause basal insulin secretion, while inhibition of secretion preserved the cells’ insulin content.14 Partial inhibition of insulin secretion in overweight mice Along with elevated fasting insulin did not result in increased glucose levels, nor did the animals fare worse on a glucose tolerance test, indicating that elevated insulin was not crucial to preserve normal levels of circulating glucose.15
Thus, evidence exists from in vitro studies and job in animal models that metabolic health and insulin secretory performance improve by preventing hyperinsulinemia or lowering the quantity of ingested long-chain fatty acids. These approaches are now moving in to clinical testing, Along with some early success.
Predicting and treating diabetes
Insulin secreted by the pancreas travels initial to the liver, where it suppresses hepatic glucose production and is degraded. As a result, blood insulin levels entering the liver are three times higher compared to the concentrations that ultimately reach the periphery. This may cause hepatic insulin resistance to occur prior to muscle insulin resistance. To deliver adequate insulin supplies to the liver to conquer such insulin resistance, then, needs the administration of three times a lot more insulin compared to is normally found in the periphery. Such excess insulin worsens muscle insulin resistance and promotes triglyceride synthesis, leading to enhances in physique fat and weight gain that further perpetuate metabolic dysfunction. Higher insulin levels may likewise promote cell growth and proliferation, increasing one’s risk of cancer.
Several small studies have actually assessed the effects of inhibiting insulin secretion to maintain β-cell insulin content in overweight and prediabetic subjects. A study in healthy and balanced men showed a lower glucose level during an oral glucose tolerance test following a single dose of NN414, a small molecule that inhibits release of insulin from β cells;16 yet another study documented improved glucose-stimulated insulin secretion in diabetics after seven days of treatment Along with diazoxide, which has actually the same effect as NN414.17 Paired Along with exogenous insulin to preserve normal glucose levels, decreasing β-cell stimulation may likewise tips maintain the remaining β-cell function in type 1 diabetics, whose metabolic dysfunction stems from an autoimmune attack on the pancreatic islets.18 (See “Taming Autoimmunity,” The Scientist, June 2016.)
Standard therapies adopted by medical practitioners may actually be causing metabolic dysfunction.
A few human studies have actually indicated that reversing hyperlipidemia can easily likewise stall the development of diabetes. As seen in animal models, consumption of medium-chain triglycerides (such as those found in palm kernel oil and coconut oil), as opposed to long-chain triglycerides (such as those in olive oil), increased energy expenditure, satiety, and weight-loss in overweight humans.4 More-extensive, longer trials are required to identify patients that would certainly benefit from such dietary intervention. Experimentally reducing carbohydrates in the diet of prediabetic and diabetic patients is likewise a promising strategy, as carbohydrates are crucial to form triglycerides, and most cells burn fat if glucose is not available.
PPARα agonists, particularly fenofibrate, have actually been inconsistent in their effects in human trials. Yet bezafibrate, a fibrate that interacts Along with all three PPAR isoforms (α, β, and γ), has actually consistently lowered triglycerides and improved glucose handling in diabetics.19,20,21 It must be noted, however, that most fibrate studies were designed to assess cardiac outcomes; the use of fibrates specifically to Avoid deterioration of metabolic health prior to the onset of overt diabetes has actually not been studied in humans.
Unfortunately, the field has actually been slow to adopt hyperlipidemia and hyperinsulinemia as prime targets for diabetes therapy. It’s difficult to adjustment scientific thinking, and most researchers are still stuck on insulin resistance as the ultimate molecular cause of metabolic dysfunction. Yet modern treatments often worsen prognosis. The time has actually come to focus on ways to protect the β cell, and research is now revealing merely how to do that. Diverse stem cell therapies in development that are designed to stimulate the production of brand-new β cells could likewise improve pancreatic function. We ought to follow the science as it leads us in brand-new directions, and thoroughly test some of these novel approaches that have actually begun to reveal promise.
Barbara E. Corkey is Zoltan Kohn Professor of Medicine, Director of the Obesity Research Focus and Vice Chair for Research in the Department of Medicine at Boston University School of Medicine. She would certainly like to express special appreciation to Dylan Thomas, Marie McDonnell, Richard Corkey, and Stanley Schwartz for their valuable tips on this article.
References
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- S. Del Prato et al., “Effect of sustained physiologic hyperinsulinaemia and hyperglycaemia on insulin secretion and insulin sensitivity in man,” Diabetologia, 37:1025-35, 1994.
- B.E. Corkey, J.T. Deeney, “Acyl CoA regulation of metabolism and signal transduction,” Prog Clin Biol Res, 321:217-32, 1990.
- M.P. St-Onge, P.J. Jones, “Physiological effects of medium-chain triglycerides: Potential agents in the prevention of obesity,” J Nutr, 132:329-32, 2002.
- F.P. Mancini et al., “Fenofibrate prevents and reduces physique weight gain and adiposity in diet-induced overweight rats,” FEBS Lett, 491:154-58, 2001.
- C. Weyer et al., “a higher fasting plasma insulin concentration predicts type 2 diabetes independent of insulin resistance: Evidence for a pathogenic role of relative hyperinsulinemia,” Diabetes, 49:2094-101, 2000.
- G. Gulli et al., “The metabolic profile of NIDDM is fully established in glucose-tolerant offspring of two Mexican-American NIDDM parents,” Diabetes, 41:1575-86, 1992.
- S.M. Haffner et al., “Decreased insulin secretion and increased insulin resistance are independently related to the 7-year risk of NIDDM in Mexican-Americans,” Diabetes, 44:1386-91, 1995.
- S. Lillioja et al., “Insulin resistance and insulin secretory dysfunction as precursors of non–insulin-dependent diabetes mellitus. Prospective studies of Pima Indians,” N Engl J Med, 329:1988-92, 1993.
- R.A. Sicree et al., “Plasma insulin response among Nauruans: Prediction of deterioration in glucose tolerance over 6 yr,” Diabetes, 36:179-86, 1987.
- 1W.J. Pories, G.L. Dohm, “Diabetes: have actually we got it all wrong?” Diabetes Care, 35:2438-42, 2012.
- R. Gutman et al., “Diazoxide prevents the development of hormonal and metabolic abnormalities present in rats fed a sucrose rich diet,” Horm Metab Res, 17:491-94, 1985.
- K. Maedler et al., “Glucose- and interleukin-1 β-induced β cell apoptosis needs Ca2+ influx and extracellular signal–regulated kinase (ERK) 1/2 activation and is prevented by a sulfonylurea receptor 1/inwardly rectifying K+ channel 6.2 (SUR/Kir6.2) selective potassium channel opener in human islets,” Diabetes, 53:1706-13, 2004.
- K.A. Erion et al., “Chronic exposure to excess nutrients left-shifts the concentration dependence of glucose-stimulated insulin secretion in pancreatic β cells,” J Biol Chem, 290;16191-201, 2015.
- R. Alemzadeh, K.M. Tushaus, “Modulation of adipoinsular axis in prediabetic zucker diabetic fatty rats by diazoxide,” Endocrinology, 145:5476-84, 2004.
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- E. Qvigstad et al., “Nine weeks of bedtime diazoxide is well tolerated and improves beta-cell function in subjects Along with Type 2 diabetes,” Diabet Med, 21:73-76, 2004.
- M.A. Radtke et al., “6 months of diazoxide treatment at bedtime in newly diagnosed subjects Along with type 1 diabetes does not influence parameters of β cell function and autoimmunity Yet improves glycemic control,” Diabetes Care, 33:589-94, 2010.
- J.H. Flory et al., “Antidiabetic action of bezafibrate in a large observational database,” Diabetes Care, 32:547-51, 2009.
- H. Tenenbaum et al., “Long-term effect of bezafibrate on pancreatic beta cell function and insulin resistance in patients Along with diabetes,” Atherosclerosis, 194:265-71, 2007.
- T. Teramoto et al., “Effects of bezafibrate on lipid and glucose metabolism in dyslipidemic patients Along with diabetes: The J-BENEFIT study,” Cardiovasc Diabetol, 11:29, 2012.
