Inflammation: The Root of all Evil in Diabetes and the Dysmetabolic Syndrome

Aaron I. Vinik, MD, PhD, FCP, FACP

Disclosures

December 21, 2004

Editorial Collaboration

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At this year's EASD Meeting, the Camillo Golgi lecture was given by Professor Antonio Ceriello, Chair of Internal Medicine, University of Udine, Italy. Professor Ceriello has systematically studied the role of oxidative stress as a contributor to insulin resistance, as well as a possible factor affecting pancreatic islet dysfunction.[1] He proposed that free radicals were generated in excess, causing inflammation damaging to the endothelium of muscle, fat, and pancreatic islets. This concept thus implicates inflammation in both sides of the equation leading to the dysmetabolic syndrome and culminating in type 2 diabetes -- notably insulin resistance and impaired beta-cell function.

My colleagues and I at The Strelitz Diabetes Institutes have suggested a flow of events that begins with an underlying genetic predisposition of increased susceptibility to oxidative and nitrosative stress induced by environmental factors such as overfeeding or smoking.[2] Inflammation plays an important role early (eg, contributing to oxidative injury) and throughout the pathogenesis of microvascular complications. Lipotoxicity and glucotoxicity, the formation of advanced glycation end products, and epigenetic phenomena occur later in the evolution of the dysmetabolic syndrome and diabetes (Figure 1).

Figure 1. Evolution of the dysmetabolic syndrome and diabetes.[2]

Insulin (whether endogenous, exogenous, alone, or enhanced by sensitization) has an important role in preventing the formation of deleterious imprinting through direct anti-inflammatory effects, as well as through control of glycemia, dyslipidemia, and the epigenetic consequences.

The early metabolic environment, even prior to the development of impaired glucose tolerance, has influence on the subsequent development of macrovascular disease (LeRoith D, Fonseca V, Vinik A. Hypothesis: Early metabolic control alters the natural history of diabetic vascular complications. 2004. Submitted for publication). The Framingham Offspring Study[3] and the European Prospective Investigation into Cancer (EPIC) Norfolk[4] study revealed that even among subjects with normal glucose tolerance, metabolic risk increased continuously across 5 quintiles of fasting glucose within the nondiabetic range. Long-term follow-up of patients from the San Antonio Heart Study who were nondiabetic at baseline revealed that atherogenic changes, such as lipid abnormalities and resistance to the action of insulin, precede the onset of hyperglycemia by many years and significantly contribute to the risk of subsequent macrovascular complications.[5]

Insulin resistance and the associated elevations of inflammatory mediators such as interleukin-6 and C-reactive protein are strongly predictive of diabetes.[6,7,8] The link to adverse macrovascular outcome may be that subjects with insulin resistance have impaired endothelial nitric oxide (NO) production, and consequently experience enhanced inflammation and oxidative stress. [9,10] Similarly, it is now apparent that increased production of NO leads to nitrosative stress and damages the pancreatic beta cell.[11] Thus, the inflammatory changes and insulin resistance that precede the advent of hyperglycemia are important factors in the early metabolic environment, contribute to the formation of metabolic memory, and are targets for early intervention.

Direct Anti-inflammatory Effects of Insulin and Insulin Sensitizers

Evidence suggests that insulin has anti-inflammatory effects, including suppression of intercellular adhesion molecule 1 and monocyte chemoattractant protein 1, decreased generation of reactive oxidative species, and inhibition of the transcription factor nuclear factor, which induces the transcription of cytokines and enzymes integral to both inflammation and oxidative stress.[2,12] The question that arises is whether insulin sensitizers can suppress markers of inflammation prior to the development of diabetes. If this were the case, then not only would the insulin-sensitizing glitazones enhance the disposal of glucose -- a necessary ingredient to combat the hyperglycemia of diabetes -- they also would have the ability to preserve beta-cell function.

Preservation of Beta-cell Function of Insulin and Insulin Sensitizers

The United Kingdom Prospective Diabetes Study established that at the time of diagnosis of type 2 diabetes, patients had already lost 50% of their beta-cell function.[13] Furthermore, despite interventions with sulfonylureas and biguanides, there was a progressive loss of 5% to 10% of beta-cell function per year, so that within 10 to 20 years, all patients would be insulin depleted and require insulin replacement therapy. Clearly, the effort to enhance glucose disposal alone in diabetes is insufficient to mitigate the progressive nature of the condition.

Yazawa and colleagues[14] of Saitama Medical College in Japan sought to determine in 32 control subjects and 164 patients with type 2 diabetes if there were differences in the proinsulin/insulin (PI/I) molar ratio as an indicator of beta-cell exhaustion or iatrogenically induced beta-cell dysfunction. Their type 2 diabetic subjects comprised a group of 82 treated with diet alone; 24 treated with large doses of sulfonylureas (glibenclamide > 3.75 mg/day, glimepiride > 3 mg/day, and gliclazide > 120 mg/day); 46 treated with low-dose sulfonylureas; and 12 subjects treated with drugs other than sulfonylureas. They found no differences in the PI/I molar ratios between controls and diet-treated people with type 2 diabetes. The use of high-dose sulfonylureas increased the ratio, whereas low-dose sulfonylureas and use of drugs other than sulfonylureas did not increase this ratio. Duration of diabetes was also associated with progressive reduction in insulin secretion. The investigators concluded that the use of high-dose sulfonylureas promotes premature exhaustion of the beta cell. This is akin to flogging a tired horse, and seems anathema to those thinking of winning the race against the inexorable course of diabetes. Clearly, the use of agents that have the ability to preserve beta-cell function, possibly via an anti-inflammatory mode of action, would be desirable. Even more attractive would be the preservation of beta-cell function and/or mass at a time when it has not been grossly depleted by the diabetic or inflammatory process. Such a window of opportunity (see ellipse in Figure 2) presents itself during the evolution of diabetes from the dysmetabolic syndrome.

Figure 2. The window of opportunity for intervention in type 2 diabetes.

Jin and colleagues[15] of Sichuan University in Chengdu, China, examined the effects of 4 months of treatment with pioglitazone, an insulin sensitizer, in 22 patients with the dysmetabolic syndrome and impaired glucose tolerance. While their subjects tended to be lean, unlike those encountered in other parts of the world, they did fulfill current criteria for the syndrome and had normal A1Cs. Insulin secretion was studied using a rapidly sampled intravenous glucose tolerance test, and resistance to the action of insulin was measured using a hyperinsulinemic clamp. Four months of treatment reduced insulin resistance at a lower cost of insulin production. This was accompanied by an elevation of high-density lipoprotein cholesterol and a lowering of triglycerides, albeit with a rise in low-density lipoprotein cholesterol. Ancillary measurements included markers of inflammation such as C-reactive protein, TNFalpha, and IL-6, as well as white blood cell count and erythrocyte sedimentation rate, which improved. The investigators conclude that pioglitazone can preserve beta-cell function in dysmetabolic syndrome, possibly by decreasing the inflammatory environment. This clearly raises the possibility that, in susceptible people at high risk, we might embark on quantitation of the inflammatory risk profile and consider preventive treatment of those at great risk of developing type 2 diabetes. Would this then work if we used glitazones in the more aggressive forms of diabetes in which there is an autoimmune destruction of the beta-cell mass?

Zhou and colleagues[16] of the Central South University of Changsha, China, examined the ability of rosiglitazone to preserve beta-cell function in non-insulin-dependent subjects with latent autoimmune diabetes of adults (LADA). LADA patients with a type 2 phenotype who were glutamic acid decarboxylase antibody positive (GAD) with fasting C peptide of > 0.3 nmol/L and diabetes of < 5 years' duration were randomly assigned to receive sulfonylurea (n = 18) or rosiglitazone (n = 19). Patients have been followed for 6, 12, and 18 months. Blood samples for glucose, insulin, and C-peptide were drawn at 6-month intervals, and 75-g oral glucose tolerance tests were performed. In the sulfonylurea-treated group, there was a progressive decline in insulin secretion measured either by the C-peptide response or the homeostasis model assessment of insulin sensitivity (HOMA-IS). By contrast, in the rosiglitazone-treated patients, there was a decrease in HOMA insulin resistance (HOMA-IR). At the 18-month visit, the rosiglitazone-treated patients had an increase in HOMA-IS and in the C-peptide response to glucose ingestion. Using multiple variables and a stepwise progressive regression analysis, only the GAD titer and the treatment groups were determinants of this difference in response. The authors rightfully conclude that only rosiglitazone and not sulfonylureas preserve beta-cell function in patients with LADA. While this finding was very exciting, the means whereby it was achieved were not identified. GAD antibodies are probably not directly responsible for the beta-cell destruction in this syndrome but rather serve as a surrogate for the underlying autoimmune process. Nonetheless, the findings reiterate the notion that this class of drugs may have anti-inflammatory effects capable of preserving beta cells even in the face of an autoimmune assault. The question then arises: "Is this a hardy response that is robust enough to stand the test of time?"

To address this issue, Vinik and colleagues[17] examined the effects of rosiglitazone on pancreatic beta-cell function and insulin resistance in older type 2 diabetes mellitus patients being treated with sulfonylureas. In a multicenter trial in 215 subjects with type 2 diabetes aged 59 to 89 years with features of the dysmetabolic syndrome including obesity, hyperglycemia, and diabetic dyslipidemia, subjects were randomized to receive either glipizide (SU) plus placebo (n = 110) or glipizide plus rosiglitazone (RSG), with an uptitration regimen for RSG or SU if the blood glucose exceeded > 10 mmol/L. The HOMA-IR and HOMA beta-cell function were assessed at baseline and at study end after 2 years of treatment. Maximum dose of SU was 40 mg/day, and maximum dose of RSG was 4 mg twice daily. In addition to these indices, a novel approach to allow for the dependence of insulin secretion on the degree of insulin resistance, namely the insulin secretion index (ISI)/ HOMA-IR, was used as a measure of the change in insulin secretory capacity as a function of the resistance to the action of insulin. Uptitration of SU did not lower A1C, whereas addition of RSG lowered it by 0.65% -- an effect that persisted for 2 years. HOMA-IR increased by 17.76 % in the SU group and decreased by 13.79% with RSG treatment, demonstrating the cardinal difference between SU and RSG on effects on insulin resistance. Perhaps of greatest moment was the small increase in HOMA-ISI with treatment with SU of 6.44%, particularly since we have come to recognize that the action of SU is to stimulate pancreatic beta-cell function; whereas, paradoxically, an agent (RSG) expected only to lower insulin resistance increased insulin secretory capacity by 55%, measured as the HOMA ISI. Finally ISI/HOMA fell by 14% in the SU-treated subjects but rose by 10.9 % with RSG, demonstrating that despite the reduction in insulin resistance that would generate a lesser need for insulin secretion, RSG enhanced this capacity. In other words, the addition of RSG to SU had a durable effect on reducing insulin and improving pancreatic beta-cell function compared with SU alone, which had deleterious effects on beta-cell function. Thus, it appears that the addition of RSG to SU, even in older subjects with compromised beta-cell function, is capable of improving that function and, in so doing, seems to abrogate the progressive decline in beta-cell function characteristic of the disease.

Conclusion

The progressive nature of type 2 diabetes is not related to further increase in insulin resistance but rather to a decline in beta-cell function. The mechanism of beta-cell dysfunction appears to include inflammation involving TNFalpha, C-reactive protein, increased white blood cell count and erythrocyte sedimentation rate, autoimmunity (GAD antibodies) in the LADA syndrome, and a replacement of islets by islet amyloid protein. All therapies thus far have addressed the insulin-resistant component of type 2 diabetes or have been directed at stimulating beta cells or changing hepatic glucose output. It now seems feasible that the causes of progressive decline in beta-cell function can be addressed using agents that target the many contributors to its demise. This information may call for a paradigm shift wherein the earlier recognition of the inflammatory status of the predisposed individual at risk for the development of type 2 diabetes would be evaluated and prophylactic therapy embarked upon. This hypothesis would of course need to be tested in large-scale clinical trials before being implemented in the clinical care of people with the dysmetabolic or prediabetes syndromes.

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