Pathogenesis of Type 2 Diabetes Mellitus

ABSTRACT

Numerous distinct pathophysiologic abnormalities have been associated with type 2 diabetes mellitus (T2DM). It is well established that decreased peripheral glucose uptake (mainly muscle) combined with augmented endogenous glucose production are characteristic features of insulin resistance. Increased lipolysis, elevated free fatty acid levels, along with accumulation of intermediary lipid metabolites contributes to further increase glucose output, reduce peripheral glucose utilization, and impair beta-cell function. Adipocyte insulin resistance and inflammation have been identified as important contributors to the development of T2DM. The presence of non-alcoholic fatty liver disease [NAFLD] is now considered an integral part of the insulin resistant state. The traditional concepts of “glucotoxicity” and lipotoxicity, which covers the process of beta cell deterioration in response to chronic elevations of glucose and lipids, has been expanded to encompass all nutrients [‘nutri-toxicity”]. The delayed transport of insulin across the microvascular system is also partially responsible for the development of tissue insulin resistance. Compensatory insulin secretion by the pancreatic beta cells may initially maintain normal plasma glucose levels, but beta cell function is already abnormal at this stage, and progressively worsens over time. Concomitantly, there is inappropriate release of glucagon from the pancreatic alpha-cells, particularly in the post-prandial period. It has been postulated that both impaired insulin and excessive glucagon secretion in T2DM are secondary to an “incretin defect”, defined primarily as inadequate release or response to the gastrointestinal incretin hormones upon meal ingestion. To a certain extent, the gut microbiome appears to play a role in the hormonal and metabolic disturbances seen in T2DM. Moreover, hypothalamic insulin resistance (central nervous system) also impairs the ability of circulating insulin to suppress glucose production, and renal tubular glucose reabsorption capacity may be enhanced, despite hyperglycemia. These pathophysiologic abnormalities should be considered for the treatment of hyperglycemia in patients with T2DM. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

NORMAL GLUCOSE HOMEOSTASIS

In the post-absorptive state (10-12 hour overnight fast), the majority of total body glucose disposal takes place in insulin independent tissues (1). Under basal conditions, approximately 50% of all glucose utilization occurs in the brain, which is insulin independent and becomes saturated at a plasma glucose concentration of about 40 mg/dl (2). Another 25% of glucose uptake occurs in the splanchnic area (liver plus gastrointestinal tissues) and is also insulin independent (3). The remaining 25% of glucose metabolism in the post-absorptive state takes place in insulin-dependent tissues, primarily muscle (4,5). Basal glucose utilization averages ~2.0 mg/kg.min and is precisely matched by the rate of endogenous glucose production (1,3-7). Approximately 85% of endogenous glucose production is derived from the liver, and the remaining amount is produced by the kidney (1,8,9). Approximately one-half of basal hepatic glucose production is derived from glycogenolysis and one-half from gluconeogenesis (9,10).

Following glucose ingestion, the balance between endogenous glucose production and tissue glucose uptake is disrupted. The increase in plasma glucose concentration stimulates insulin release from the pancreatic beta cells, and the resultant hyperinsulinemia and hyperglycemia serve (i) to stimulate glucose uptake by splanchnic (liver and gut) and peripheral (primarily muscle) tissues and (ii) to suppress endogenous glucose production (1,3-7,11-14).

Hyperglycemia, in the absence of hyperinsulinemia, exerts its own independent effect to stimulate muscle glucose uptake and to suppress endogenous glucose production in a dose dependent fashion (14-16). The majority (~80-85%) of glucose that is taken up by peripheral tissues is disposed of in muscle (1,3-7,11-14), with only a small amount (~4-5%) being metabolized by adipocytes (17). Although fat tissue is responsible for only a fraction of total body glucose disposal, it plays a very important role in the maintenance of total body glucose homeostasis (see below). Insulin is a potent inhibitor of lipolysis and even small increments in the plasma insulin concentration exerts a potent anti-lipolytic effect, leading to a marked reduction in the plasma free fatty acid level (18). The decline in plasma FFA concentration results in increased glucose uptake in muscle (19) and contributes to the inhibition of endogenous glucose production (16,20). Thus, changes in the plasma FFA concentration in response to increased plasma levels of insulin and glucose play an important role in the maintenance of normal glucose homeostasis (21,22).

SITE OF INSULIN RESISTANCE IN TYPE 2 DIABETES (T2DM)

The maintenance of whole-body glucose homeostasis is dependent upon a normal insulin secretory response by the pancreatic beta cells and normal tissue sensitivity to the independent effects of hyperinsulinemia and hyperglycemia (i.e., the mass-action effect of glucose) to augment glucose uptake. In turn, the combined effects of insulin and hyperglycemia to promote glucose disposal are dependent on three tightly coupled mechanisms: (i) suppression of endogenous (primarily hepatic) glucose production; (ii) stimulation of glucose uptake by the splanchnic (hepatic plus gastrointestinal) tissues; and (iii) stimulation of glucose uptake by peripheral tissues, primarily muscle (1,4,14). Muscle glucose uptake is regulated by flux through two major metabolic pathways: glycolysis (of which ~90% represents glucose oxidation) and glycogen synthesis.

DYNAMIC INTERACTION BETWEEN INSULIN SENSITIVITY AND INSULIN SECRETION IN T2DM

Subjects with T2DM manifest abnormalities both in tissue (muscle, fat, and liver) sensitivity to insulin and in pancreatic insulin secretion. To understand how these two metabolic disturbances interact to produce the full-blown diabetic condition, it is necessary to quantitate insulin action and insulin secretion in the same individual over a wide range of insulin sensitivity. This dynamic interaction is demonstrated graphically by results obtained in healthy, lean, young normal glucose tolerant women who received a euglycemic insulin clamp (1 mU.kg^-1.min^-1) and were stratified into quartiles based upon the rate of insulin-mediated glucose disposal (49).

Insulin secretion was measured independently on a separate day with a +125 mg/dl hyperglycemic clamp. Insulin resistance and insulin secretion were strongly and positively correlated (r=0.79, p<0.001). Women who were the most insulin resistant (quartile 1) had the highest fasting plasma insulin concentrations and highest early and late phase plasma insulin responses. Similar results relating the plasma insulin response and the severity of insulin resistance have been reported in normal glucose tolerant subjects with the minimal model technique (46,47) and the insulin suppression test/oral glucose tolerance test (214).

A number of groups have examined the dynamic interaction between insulin secretion and insulin sensitivity in subjects with T2DM (1,4,34,35,38,39,42,46-48,58-61,150,162).

DeFronzo (4) studied lean (ideal body weight < 120%) and obese (ideal body weight > 125%) subjects with varying degrees of glucose tolerance as follows: Group I-obese subjects (n=24) with normal glucose tolerance; Group II-obese subjects (n=23) with impaired glucose tolerance; Group III-obese subjects (n=35) with overt diabetes, subdivided into those with a hyperinsulinemic response and those with a hypoinsulinemic response during a 100-gram OGTT; Group IV-normal weight subjects with T2DM (n=26); Group V-normal weight subjects (n=25) with normal glucose tolerance. All subjects ingested 100 g of glucose to provide a measure of glucose tolerance and insulin secretion. Whole-body insulin sensitivity was quantitated with the euglycemic insulin (~100 µU/ml) clamp technique, which was performed with indirect calorimetry to quantitate rates of glucose oxidation and non-oxidative glucose disposal. The later primarily reflects glycogen synthesis (215).

In normal weight subjects with T2DM, insulin-mediated whole-body glucose uptake was reduced by 40-50% and the impairment in insulin action resulted from defects in both oxidative and non-oxidative glucose metabolism (4). Obese individuals without T2DM were as insulin resistant as the normal-weight subjects with T2DM (4). Defects in both glucose oxidation and glucose storage contributed to the insulin resistance in the obese nondiabetic group. From the metabolic standpoint, therefore, obesity and T2DM closely resemble each other.

Similar results concerning reduced whole-body insulin sensitivity in individuals with obesity and T2DM have been reported by other investigators (160,161,166,216-218). Despite nearly identical degrees of insulin resistance, normal-weight subjects with T2DM manifested fasting hyperglycemia and marked glucose intolerance, whereas the obese individuals without diabetes had normal or only minimally impaired oral glucose tolerance (4). This apparent paradox is explained by the plasma insulin response during the OGTT. Compared with control subjects, the obese group without diabetes secreted more than twice as much insulin, and this was sufficient to offset the insulin resistance. In contrast, in normal-weight subjects with T2DM, the pancreas, when faced with the same challenge, was unable to augment its secretion of insulin sufficiently to compensate for the insulin resistance. This imbalance between insulin supply by the beta-cells and the insulin requirement by tissues resulted in a frankly diabetic state, with fasting hyperglycemia and marked glucose intolerance.

The fact that plasma insulin response to the development of insulin resistance typically is increased during the natural history of T2DM does not mean that the beta cell is functioning normally. To the contrary, recent studies (4C) have demonstrated that the onset of beta-cell failure occurs much earlier and is more severe than previously appreciated.

Recognizing that simply measuring plasma insulin response to a glucose challenge does not provide a valid index of beta cell function, a series of studies were conducted in subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and T2DM, using an oral glucose tolerance test to evaluate the increment in insulin secretion in response to an increment in plasma glucose. A euglycemic insulin clamp to measure insulin sensitivity was also performed to address the adjustment of the beta cell to the body’s sensitivity to insulin.

Thus, the results yielded a better measure of beta-cell function expressed per increment of plasma glucose and corrected for the degree of insulin resistance, the so-called disposition index [ΔI/ΔG ÷IR]. These data revealed a substantial decrease in beta-cell function, most evident in individuals with IGT who had lost anywhere from 60 to 85% of the total insulin secretory capacity.

When obesity and diabetes coexist in the same individual, the severity of insulin resistance is only slightly greater than that in either the normal-weight diabetic or nondiabetic obese groups (4), and the magnitude of the defects in glucose oxidation and non-oxidative glucose disposal are similar in all obese and diabetic groups. Although hyperinsulinemic and hypoinsulinemic obese diabetic subjects were equally insulin resistant, the severity of glucose intolerance is worse in the hypoinsulinemic group, and this was related entirely to the presence of severe insulin deficiency.

In the obese nondiabetic subjects, tissue sensitivity to insulin is markedly reduced, but glucose tolerance remains perfectly normal because the beta cells are able to augment their insulin secretory capacity appropriately to offset the defect in insulin action. As the obese individual develops impaired intolerance, there is a further reduction in insulin-mediated glucose disposal, which is due primarily to a decrease in glycogen synthesis. However, there is only a small additional impairment in glucose tolerance, because the beta cells are able to further augment their secretion of insulin to counteract the deterioration in insulin sensitivity. The progression of the obese, glucose intolerant person to overt diabetes is heralded by a decline in insulin secretion without any worsening of insulin resistance. The obese diabetic has tipped over the top of Starling's curve of the pancreas and is now on the descending portion. Even though the plasma insulin response is increased compared to nondiabetic control subjects, it is not elevated appropriately for the degree of insulin resistance and there is evidence that there is ~80% of beta-cell functional loss by the time of diagnosis in diabetic subjects. The beta cell insulin response during the OGTT is best represented by the change in plasma insulin over the change in plasma glucose concentration, taking into consideration the degree of insulin resistance for each individual, the so-called Insulin Secretion /Insulin Resistance Index or Disposition Index as shown in Figure 1 below.

Figure 1

- Log normalization of the relationship between 2-hour plasma glucose and Insulin Secretion/ Insulin Resistance in subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and patients with type 2 diabetes (T2DM). There is a linear decline in the insulin secretory capacity with the development of the disease, such that by the time clinical diabetes with hyperglycemia become evident, the loss of beta-cell secretion of insulin is below 5% of NGT controls.

The natural history of T2DM described above is consistent with results in humans and monkeys published by other investigators (33-39,42,43,59-61,98,150). In lean subjects with a wide range of glucose tolerance, Reaven et al (42) demonstrated that the progression from normal to impaired glucose tolerance was marked by the development of severe insulin resistance, which was counterbalanced by a compensatory increase in insulin secretion. The onset of T2DM was associated with no (or only slight) further deterioration in tissue sensitivity to insulin. Rather, insulin secretion declined and the impairment in beta cell function was paralleled by a decrease in glucose tolerance. A similar sequence of events has been documented prospectively in Pima Indians (34-39,58,60), in Caucasians (1,4,41,42,44,47,59, 162, 219), Pima Indians (34-39,58,60,219), and Pacific Islanders (33,62,220) and, is consistent with the development of T2DM in the rhesus monkeys (48). As monkeys grow older, they become obese and develop a diabetic condition closely resembling human T2DM. The earliest detectable abnormality in this primate model is a decrease in tissue sensitivity to insulin. Because of a compensatory increase in insulin secretion, the fasting plasma glucose concentration and glucose tolerance remain normal.

The studies detailed above indicate that insulin resistance is an early and characteristic feature of the natural history of T2DM in high-risk populations. Overt diabetes develops only in those individuals whose beta cells are unable to appropriately augment their secretion of insulin to compensate for the defect in insulin action. It should be recognized, however, that there are well-described populations with T2DM in whom insulin sensitivity is normal at the onset of diabetes, whereas insulin secretion is severely impaired (81-83). How frequently this occurs in a typical patient with T2DM remains to be determined. This insulinopenic variety of diabetes appears to be more common in African-Americans, elderly subjects, and in lean Caucasians. In this later group, it is important to exclude type 1 diabetes, since ~10% of Caucasians with older onset diabetes are islet cell antibody and/or GAD positive (220).

ROLE OF THE ADIPOCYTE IN THE PATHOGENESIS OF T2DM

The majority (>80%) of persons with T2DM in the US are overweight (221). Both lean and especially obese persons with T2DM are characterized by day-long elevations in the plasma free fatty acid concentration, which fail to suppress normally following ingestion of a mixed meal or oral glucose load (222). Free fatty acids (FFA) are stored as triglycerides in adipocytes and serve as an important energy source during conditions of fasting. Insulin is a potent inhibitor of lipolysis, and restrains the release of FFA from the adipocyte by inhibiting the enzyme hormone sensitive lipase. In patients with T2DM the ability of insulin to inhibit lipolysis (as reflected by impaired suppression of radioactive palmitate turnover) and reduce the plasma FFA concentration is markedly reduced (17). It is now recognized that chronically elevated plasma FFA concentrations can lead to insulin resistance in muscle and liver (1,4,19,21,22,51,162,223,224) and impair insulin secretion (22,225,226). Thus, elevated plasma FFA levels can cause/aggravate three major pathogenic disturbances that are responsible for impaired glucose homeostasis in individuals with T2DM and the "triumvirate" (muscle, liver, beta cell) was joined by the "fourth musketeer" (227) to form the "disharmonious quartet". In addition to FFA that circulate in plasma in increased amounts, individuals with T2DM and obese individuals without T2DM have increased stores of triglycerides in muscle (228,229) and liver (230,231) and the increased fat content correlates closely with the presence of insulin resistance in these tissues. Triglycerides in liver and muscle are in a state of constant turnover and the metabolites (i.e., fatty acyl CoAs) of intracellular FFAs have been shown to impair insulin action in both liver and muscle (1,4,92). This sequences of events has been referred to as "lipotoxicity" (1,4,22,93). Evidence also has accumulated to implicate "lipotoxicity" as an important cause of beta cell dysfunction (22,93) (see earlier discussion).

THE OMNIOUS OCTET

Figure 2.

Summary of the Eight Principal Mechanisms Contributing to Hyperglycemia in Patients with Type 2 Diabetes

The eight principle known causes leading to hyperglycemia through the pathogenesis of T2DM are summarized in Figure 2. It is already established that decreased peripheral glucose uptake combined with augmented endogenous (hepatic) glucose production are characteristic features of insulin resistance. Increased lipolysis with accumulation of intermediary lipid metabolites contributes to further enhance glucose output while reducing peripheral utilization. Compensatory insulin secretion by the pancreatic beta-cells eventually reaches a maximum and, then it progressively deteriorates. Concomitantly, there is inappropriate release of glucagon from the pancreatic alpha-cells, particularly in the post- prandial period. It has been postulated that both impaired insulin and excessive glucagon secretion in T2DM are facilitated by the “incretin defect”, defined primarily as inadequate response of the gastrointestinal “incretin” hormones to meal ingestion in addition to islet-cell resistance to the potentiating action on insulin-secretion by these gastrointestinal peptides. Moreover, considering that hypothalamic insulin resistance (central nervous system) with an elevated sympathetic drive, typically seen in patients with T2DM also impair the ability of circulating insulin to suppress glucose production. The fact that renal tubular glucose reabsorption capacity is enhanced in diabetic patients also contributes to the development and maintenance of chronic hyperglycemia. Thus, the time has arrived to advance the concept from the “triumvirate” to the “omnious octet” (4A). Further, recent observations have recognized that a chronic low-grade inflammation with activation of the immune system are involved in the pathogenesis of obesity-related insulin resistance and T2DM (4D). Adipose tissue, liver, muscle and pancreas are themselves sites of inflammation in presence of obesity. Infiltration of macrophages and other immune cells as well as the presence of pro-inflammatory cytokines in these tissues has been associated with insulin resistance and beta-cell impairment. The possibility that endothelial dysfunction and changes in vascular capillary permeability affect peripheral insulin action has also been raised (4E). These pathogenic mechanisms must be taken into account when deciding for the treatment of hyperglycemia in patients with T2DM.

CELLULAR MECHANISMS OF INSULIN RESISTANCE

The stimulation of glucose metabolism by insulin requires that the hormone must first bind to specific receptors that are present on the cell surface of all insulin target tissues (1,274-277). After insulin has bound to and activated its receptor, "second messengers" are generated and these second messengers initiate a series of events involving a cascade of phosphorylation- de-phosphorylation reactions (1,274-280) that eventually result in the stimulation of intracellular glucose metabolism. The initial step in glucose metabolism involves activation of the glucose transport system, leading to influx of glucose into insulin target tissues, primarily muscle (1,281,282). The free glucose, which has entered the cell, subsequently is metabolized by a series of enzymatic steps that are under the control of insulin. Of these, the most important are glucose phosphorylation (catalyzed by hexokinase), glycogen synthase (which controls glycogen synthesis), and phosphofructokinase (PFK) and PDH (which regulate glycolysis and glucose oxidation, respectively).

Glucose Transport

Activation of the insulin signal transduction system in insulin target tissues leads to the stimulation of glucose transport. The effect of insulin is brought about by the translocation of a large intracellular pool of glucose transporters (associated with low-density microsomes) to the plasma membrane (281,282,344). There are five major, different facilitative glucose transporters with distinctive tissue distributions (281,282,345,346) (Table 1). GLUT4, the transporter regulated by insulin is found in insulin-sensitive tissues (muscle and adipocytes), has a Km of ~5 mmol/l, which is close to that of the plasma glucose concentration, and is associated with HK-II (347- 349). In adipocytes and muscle, its concentration in the plasma membrane increases markedly after exposure to insulin, and this increase is associated with a reciprocal decline in the intracellular GLUT4 pool. GLUT1 represents the predominant glucose transporter in the insulin- independent tissues (brain and erythrocytes), but also is found in muscle and adipocytes. It is located primarily in the plasma membrane, where its concentration changes little after the addition of insulin. It has a low Km (~1 mmol/l) and is well suited for its function, which is to mediate basal glucose uptake. It is found in association with HKI (347-349). GLUT2 predominates in the liver and pancreatic beta-cells, where it is found in association with a specific hexokinase, HKIV (347-350). In the beta-cell, HKIV is referred to as gluco-kinase (350,351). GLUT2 has a high Km, (~15-20 mmol/l) and, as a consequence, the glucose concentration in cells expressing this transporter rises in direct proportion to the increase in plasma glucose concentration. This characteristic allows these cells to respond as glucose sensors. In summary, each tissue has a specific glucose transporter and associated hexokinase, which allows it uniquely to carry out its specialized function to maintain whole-body glucose economy.

Table 1.

Classification of Glucose Transport and HK Activity According to their Tissue Distribution and Functional Regulation

Glucose transport activity in patients with T2DM uniformly has been found to be decreased in adipocytes (281,282,320,351,352) and muscle (281,282,354-356). In adipocytes from humans with T2DM and rodent models of diabetes, there is a severe reduction in GLUT4 mRNA and protein, and the ability of insulin to elicit a normal translocation response and to activate the GLUT4 transporter after its insertion into the cell membrane is impaired (281,282,320,353,357). In contrast, muscle tissue obtained from lean and obese subjects with T2DM exhibits normal or increased levels of GLUT4 mRNA expression and normal levels of GLUT4 protein (358-361). Moreover, acute (2- 4-h) physiological hyperinsulinemia does not increase the number of GLUT4 transporters in muscle in either healthy subjects or subjects with T2DM (358-361). Several studies have demonstrated an increase in muscle GLUT4 mRNA levels in response to insulin in control subjects (333,360), but not in subjects with T2DM (360), suggesting insulin resistance at the level of gene transcription. However, the physiological significance of the blunted increase in muscle GLUT4 mRNA levels in subjects with T2DM is unclear, since both basal and insulin- stimulated GLUT4 protein levels are normal. Large populations of subjects with T2DM have been screened for mutations in the GLUT4 gene (362,363). Such mutations are very uncommon and, when detected, have been of questionable physiologic significance.

The results summarized above indicate that the gene (GLUT4) encoding the major insulin- responsive glucose transporter and its transcriptional/translational regulation are not impaired in T2DM. However, in contrast to the normal expression of GLUT4 protein and mRNA in muscle of subjects with T2DM, every study that has examined adipose tissue has reported reduced basal and insulin-stimulated GLUT4 mRNA levels, decreased GLUT4 transporter number in all subcellular fractions, diminished GLUT4 translocation, and impaired intrinsic activity of GLUT4 (281,282,353,361,364). These observations demonstrate that GLUT4 expression in humans is subject to tissue-specific regulation. Although insulin does not increase GLUT4 expression in muscle, it stimulates the translocation of GLUT4 transporters from their intracellular location to the cell membrane (354,365,366). In humans with T2DM, the ability of insulin to stimulate GLUT4 translocation in muscle is impaired (354,367). Using a novel triple- tracer technique, the in vivo dose-response curve for the action of insulin on glucose transport in forearm skeletal muscle has been examined in nondiabetic and subjects with T2DM (368-370). Insulin-stimulated inward muscle glucose transport is severely impaired in subjects with T2DM who are studied under euglycemic conditions. The defect in glucose transport cannot be overcome by repeating the insulin clamp at each subject's normal fasting glucose (hyperglycemia) level. Since the number of GLUT4 transporters in the muscle of subjects with T2DM is normal (358-361), impaired GLUT4 translocation (281,354,367) and decreased intrinsic activity of the glucose transporter (366,371) must be responsible for the defect in muscle glucose transport. Impaired in vivo muscle glucose transport in T2DM also has been demonstrated using MRI (372) and PET (373).

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