prevention of type 2 diabetes || pathophysiology: loss of β-cell function

11D. LeRoith (ed.), Prevention of Type 2 Diabetes: From Science to Therapy, DOI 10.1007/978-1-4614-3314-9_2, © Springer Science+Business Media New York 2012

Introduction

The pathophysiology of prediabetes is a direct extension of the physiology of glucose control. In fact, all evidence indicates that progression from normoglycemia to dysglycemia to frank hyperglycemia occurs along a continuum not just of plasma glucose concentrations but also of underlying mechanisms. Therefore, the pathophys-iology of prediabetes can be described equally well as shifts in glucose tolerance category and in terms of continuous changes in glucose parameters [ 1 ] .

The glucose system is highly homeostatic, swings in plasma glucose concentrations rarely exceeding 3 mmol/L (54 mg/dL) in normal subjects. At any given time, the plasma glucose concentration represents the balance between entry of glucose into and exit from the circulation via cellular metabolism or excretion: excessive release or defective removal (or combinations of the two) will result in rising glucose levels. Entry and exit of glucose are subject to multiple regulatory mechanisms, with insulin and glucagon principally controlling entry and insulin governing exit.

The role of the endocrine pancreas in the pathophysiology of prediabetes can therefore be reduced to the following questions: Are there changes in b -cell or a -cell function (or sensitivity to these hormones)? What consequences do these changes have for glucose homeostasis?

A preliminary consideration is the unique organization of the insulin/glucagon system. For many protein and nonprotein hormones, action is modulated by at least one, often two, hierarchical hormonal feedback pathways (e.g., CRH and ACTH hormone for cortisol, GnRH and gonadotrophins for sex steroids). In these cases,

E. Ferrannini, MD (*) Department of Internal Medicine , University of Pisa School of Medicine , Via Roma, 67 , 56100 Pisa , Italy e-mail: [email protected]

A. Mari, PhD Institute of Biomedical Engineering, National Research Council , Padova , Italy

Chapter 2 Pathophysiology: Loss of b -Cell Function

Ele Ferrannini and Andrea Mari

12 E. Ferrannini and A. Mari

sensitivity is provided by the circulating hormone concentrations acting upon speci fi c hormone receptors located on target tissues as well as on the master gland of the feedback loop (e.g., the pituitary). In the case of insulin and glucagon, there is no pituitary or hypothalamic relay; target tissues control secretion directly. Thus, the circulating concentrations of substrates (mostly glucose, but also amino acids, free fatty acids, and ketone bodies), which result from insulin action on intermediary metabolism in different tissues, feed signals back to the b -cell and the a -cell. Sensitivity gating is provided by insulin and glucagon receptors on target tissues. An additional level of regulation is autocrine/paracrine in nature, i.e., insulin recep-tors on the b -cell and the a -cell, respectively.

b -Cell function

A normal b -cell integrates multiple hormonal and substrate inputs to mount a secretory response precisely geared at limiting plasma glucose excursions [ 2 ] . The chain of events leading from stimulation of biosynthesis, processing, packaging, and release of the hormone is highly complex and tightly regulated at multiple steps. Therefore, it is not surprising that the repertoire of in vivo b -cell responses is ample; corre-spondingly, no single clinical test of insulin secretion captures the overall ability of b -cells to govern glucose homeostasis.

However, modes of insulin secretory response can be categorized into two main groups, static and dynamic, simply on the basis of the time course of stimulation. By this criterion, static properties are those that represent adaptation to chronic or prolonged stimuli, such as fasting hyperglycemia, obesity, and insulin resistance; dynamic properties are those that determine the response to acute stimulation. Fasting insulin concentration and fasting secretion rate are the primary static parameters, re fl ecting the b -cell secretory setpoint. In addition, in nondiabetic subjects the total amount of insulin released over a speci fi ed period of time is directly related to fasting insulin secretion, presumably also re fl ecting the level of the setpoint: Fig. 2.1 shows this covariation in a large group of individuals in whom the deconvolution technique was used to reconstruct secretion rates from plasma C-peptide concentrations [ 3 ] .

Dynamic properties can be investigated in response to a variety of acute stimuli, the most popular being an intravenous glucose bolus (IVGTT), a hyperglycemic clamp, and oral glucose (OGTT) or mixed meal administration. Analysis of these clinical tests has been performed in a large number of variants, employing diverse doses and timing of the stimulus, sampling schedules, and data analysis. Time-honored empirical indices are the acute insulin response to an IVGTT or to a hyper-glycemic plateau (AIR, as the sum of the incremental plasma insulin or C-peptide concentrations over the fi rst 8 min following the glucose challenge) [ 4 ] , and the insu-linogenic index on the OGTT (as the ratio of plasma insulin increments at 30 min to the corresponding plasma glucose increments). It is now recognized that the use of intravenous or oral glucose as stimulus may yield different, even contrasting, infor-mation on b -cell function [ 5 ] . More insight into in vivo dynamics of insulin secretion

132 Pathophysiology: Loss of b -Cell Function

can be gained with the use of mathematical models. We have developed and validated one such model [ 6 ] , which incorporates the main features of the in vitro response of isolated rodent or human islets to glucose stimulation: glucose sensitivity, rate sensi-tivity, and potentiation. Glucose sensitivity is the dose–response of insulin release to glucose concentrations; variably modeled (e.g., as a Michaelis–Menten function), the slope of this relationship measures the ability of b -cells to sense glucose, synchro-nize, and rev up their insulin secretion accordingly. Rate sensitivity is the ability to sense the speed of change of glucose concentrations and to further augment insulin release proportionally. Potentiation is the fact that pre-exposure to glucose enhances the response to glucose itself; this phenomenon can be also thought of as a priming effect or a glucose memory. In the isolated perfused pancreas, the timing of succes-sive glucose applications is crucial for glucose potentiation: if the time interval between two stimulating glucose levels is too long, potentiation vanishes, if too short potentiation regresses to inhibition [ 7 ] . Each of these three dynamic properties of b -cell function can be demonstrated to be present in vivo in man. We shall illustrate their emergence and their role in prediabetes by using data from the RISC study [ 3 ] . This cohort of women and men of European descent, ranging in age between 30 and 60 years, were carefully phenotyped using the hyperinsulinemic euglycemic clamp technique, an IVGTT, and an OGTT. Based on the latter, the majority of the partici-pants had normal glucose tolerance (fasting glucose <6.1 mmol/L and 2-h glucose <7.8 mmol/L), roughly 10% of them had impaired glucose tolerance (IGT, fasting glucose <7.0 mmol/L and a 2-h glucose of 7.8–11.1 mmol/L), and a small group had isolated impaired fasting glucose (IFG, fasting glucose between 6.1 and 7.0 mmol/L and 2-h glucose <11.1 mmol/L). IFG and IGT are categories of prediabetes, which sometimes are lumped together as IGR (impaired glucose regulation).

Fig. 2.1 Relationship between fasting insulin secretion rate and total insulin output (over the 2 h following the ingestion of 75 g of glucose) in nondiabetic subjects ( n = 1,318). Unpublished data from the RISC study [ 43 ]


The plasma glucose and insulin excursion in response to a 75-g oral glucose load, depicted in Fig. 2.2 , are typical: an upward shift in glucose and insulin for IFG, an exaggerated and delayed response of both glucose and insulin in IGT. If the plasma insulin concentrations are plotted against the corresponding plasma glucose concentrations at each sampling time-point, one obtains loops of different shape: steep and short in the NGT group, fl atter and elongated for IFG and IGT (Fig. 2.3 ). At each plasma glucose concentration, insulin secretion rate is higher in NGT than IFG or IGT; conversely, a given insulin secretion rate intercepts the IFG/IGT loops at higher plasma glucose levels than the NGT loop. This simply means that the ability of b -cells to induce a rise in plasma hormone concentrations in response to any given increment in glucose concentrations during the test is impaired in IFG/IGT as compared to NGT individuals; this is equivalent to saying that in IFG/IGT subjects glucose sensitivity (or sensing) is compromised. Also evident from these plots is that the plasma insulin levels associated with a given glucose concentration are higher on the descending than the ascending part of the loop, i.e., at later than earlier times during the test: this systematic difference is glucose potentiation. This simple method of interpreting insulin response in the context of the corresponding glucose stimulus can be used with any format of stimulation. The mathematical model uses the C-peptide concentrations to convert plasma insulin concentrations into insulin secretion rates (by deconvolution [ 6 ] ) and then calculates the slope of the relation-ship between insulin secretion and glycemia (Fig. 2.4 ): the mean slope over the observed plasma glucose span of each individual is termed b -cell glucose sensitivity.

Fig. 2.2 Plasma glucose and insulin concentrations during a standard OGTT in subjects with normal glucose tolerance (NGT), impaired fasting glycemia (IFG), or impaired glucose tolerance (IGT). Plots are mean ± SD. Unpublished data from the RISC study [ 43 ]


Fig. 2.3 The data in Fig. 2.2 are here presented as plots of the plasma insulin against plasma glucose concentrations at each time-point of the OGTT. The loops connect the points of each group in time sequence

Fig. 2.4 The data in Fig. 2.3 are converted (by mathematical modeling) into insulin secretion rates as a function of the concomitant plasma glucose concentrations during the OGTT

Potentiation is calculated as a time-dependent modulation of the dose–response curve, but is constrained to average unity throughout the test time; the ratio of its value at 2 h to the baseline value is called potentiation factor (Fig. 2.5 ). Rate sensi-tivity is computed from the fi rst derivative of plasma glucose concentrations for successive time intervals.


An important issue is the relationship between b -cell function and insulin sensitivity. It has been argued that insulin secretory parameters must be viewed in relation to the prevailing degree of insulin sensitivity [ 8 ] . Thus, data from frequently sampled IVGTTs have been used to show an inverse relationship between AIR and S

I (i.e., the minimal-model derived parameter of insulin sensitivity). In several pub-

lications (reviewed in [ 9 ] ), this reciprocal relationship has been reported to fi t an equilateral hyperbola, and the product of AIR and S

I has been termed disposition

index: this index has been proposed to represent the inherent ability of the b -cell to cope with the extant insulin resistance. This conceptual approach has merit and but also limitations. In fact, while the mathematical relationship between the two quan-tities depends on how they are measured (and rarely is an equilateral hyperbola [ 10 ] ), the main limitation is that some parameters of b -cell function are strongly related to insulin sensitivity while others are not. For example, fasting insulin secretion and total insulin output both are inversely related to insulin sensitivity in a curvilinear fashion, with IFG/IGT subjects falling to the right of the curve of the NGT individuals (Fig. 2.6 ). This pattern is explained by the dependency of absolute insulin secretion rates on the b -cell setpoint, which, as previously noted, is an adaptive response to chronic pressure by obesity and insulin resistance; the relative position of the IFG/IGT subjects is explained by their slightly, but signi fi cantly, higher plasma glucose concentrations. In contrast, dynamic parameters such as glucose sensitivity, rate sensitivity, and potentiation are largely independent of insulin sensitivity [ 11 ] . Therefore, a full portrait of b -cell function should include analysis of both static and dynamic parameters; separate consideration of insulin sensitivity helps assessing the

Fig. 2.5 Time course of potentiation in NGT, IFG, and IGT subjects. Note that, for each series the average potentiation is constrained to average unity. The potentiation factor is therefore taken to be the ratio of the value at 2 h to that at baseline. This ratio is clearly diminished in IGT as compared to NGT or IFG


relative role of b -cell dysfunction and insulin resistance in glucose intolerance, but creating composite indices of secretion and action—such as the disposition index—may be misleading depending on which b -cell function parameter is used [ 10 ] .

b -Cell Function in Prediabetes

Modeling of the OGTT data in Figs. 2.2 and 2.3 demonstrates that b -cell glucose sensitivity is signi fi cantly reduced in both IFG and IGT subjects, possibly to a slightly greater extent in the latter than in the former (Fig. 2.7 ). In contrast, fasting insulin secretion rate and total insulin output (over 2 h following glucose ingestion) are both increased in the prediabetic groups as compared to NGT individuals (Fig. 2.8 ). Rate sensitivity is unaltered in both dysglycemic groups, whereas poten-tiation is impaired in IGT but not IFG (Fig. 2.9 ).

All in all, b -cell dysfunction in prediabetes is basically a problem of glucose sensing: b -cells do not adequately “read” the degree of glucose rise. It is impor-tant to recognize that the hyperglycemia that develops as a result of defective secretory dynamics eventually acts upon the b -cell, inducing augmented insulin release. As a consequence, prediabetes is a state of impaired b -cell function and

Fig. 2.6 Relationship between total insulin output over the 2 h following glucose ingestion and insulin sensitivity (as the M/I). The lines are the separate power function fi t for the NGT subjects and the IFG/IGT group. The intercept of the two lines are signi fi cantly different ( p < 0.0001). Data from the RISC Study [ 3 ]


Fig. 2.7 Box plots of b -cell glucose sensitivity in the NGT, IFG, and IGT group. p Values refer to the comparison with NGT

Fig. 2.8 Box plots of fasting insulin secretion rate and total insulin output in the NGT, IFG, and IGT group. p Values refer to the comparison with NGT


hyperinsulinemia/hypersecretion [ 12 ] . Ignoring the dynamic aspects of b -cell function leads to the erroneous view (also known as the Starling curve of the pan-creas [ 13 ] ) that the endocrine pancreas “copes” adequately with the prevailing insulin resistance in the early stages of dysglycemia, and that once this compensation becomes insuf fi cient—and absolute insulin secretion starts to fall—then hyperg-lycemia ensues. On the contrary, not only is a degree of b -cell incompetence present in prediabetes, but it extends to NGT [ 14 ] . As depicted in Fig. 2.10 , the relation-ship between b -cell glucose sensitivity and glucose tolerance (as the average glucose concentration during the OGTT) describes a continuum through NGT into IFG/IGT. In fact, b -cell glucose sensitivity varies manifold between individuals, while mean glucose levels vary three- to fourfold, thereby attesting to the vast operative range of the b -cell as a controller of glucose homeostasis.

An important point is that, in prediabetic individuals the defect in glucose sens-ing is more severe than can be accounted for by age. As shown in Fig. 2.11 , age is consistently and independently associated with a decline in b -cell glucose sensitiv-ity; however, IFG and IGT subject—and even more so patients with overt type 2 diabetes—fall way below the prediction of age-related glucose insensitivity.

The empirical indices of b -cell function derived from either the OGTT or the IVGTT in the same population generally support the model-derived picture.

Fig. 2.9 Box plots of rate sensitivity and potentiation factor in the NGT, IFG, and IGT group. p Values refer to the comparison with NGT


0

25

50

75

100

125

150

175

200

25 30 35 40 45 50 55 60 65

ß-c

ell g

luco

se s

ensi

tivity

(pm

ol.m

in-1

.m-2

.mM

-1)

Age (years)

IFG

IGT T2D

Fig. 2.11 Sex- and BMI-adjusted dependence of b -cell glucose sensitivity on age in the NGT segment of the RISC cohort (line of best fi t and 95% con fi dence intervals). The mean ± SD values for the IFG and IGT subjects, as well as those for a group of 133 patients with overt type 2 diabetes (T2D), are largely lower than predicted by age

The OGTT-based insulinogenic index, for example, reproduces the impaired insulin response to “early” rises in glycemia of both IFG and IGT subjects. Of interest is that even fasting serum proinsulin concentrations carry a robust predictive weight. The IVGTT-derived indices, on the other hand, perform rather poorly both in accuracy and precision (Table 2.1 ). First, the glucose excursions in response to the intravenous

Fig. 2.10 Reciprocal association between b -cell glucose sensitivity and mean plasma glucose level during an OGTT. Note the log–log scale. Line of best fi t and its 95% con fi dence intervals are shown

5

14

37

100

273

742

3 3.5 4 4.7 5.5 6.4 7.4 8.6 10 11.6 13.4

ß-c

ell g

luco

se s

ensi

tivity

(pm

ol.m

in-1

.m-2

.mM

-1)

Plasma glucose (mmol/L)

IFG/IGT

NGT


Table 2.1 Empirical indices of b -cell function in subjects with normal glucose tolerance (NGT), impaired fasting glycemia (IFG), or impaired glucose tolerance (IGT) a

NGT ( n = 1,154) IFG ( n = 32) IGT ( n = 121) p

Empirical indices Insulinogenic index (OGTT)

(pmol/mmol) 79 [72] 53 [54] 58 [53] <0.0001

∂AUC G (IVGTT) (mmol/L) 6.80 ± 0.07 7.56 ± 0.41 a 7.56 ± 0.21 a <0.001

∂AUC I (IVGTT) (pmol/L) 90 [183] 41 [246] 89 [154] ns

∂AUC C-pep

(IVGTT) (pmol/L) 714 [606] 524 [649] 682 [538] ns ∂AUC

C-pep /∂AUC

G (IVGTT)

(pmol/mmol) 106 [83] 83 [85] 90 [65] <0.02

∂AUC I /∂AUC

G (IVGTT)

(pmol/mmol) 14 [26] 6 [35] 11 [19] ns

∂AUC secr

/∂AUC G (IVGTT)

(pmol/min m 2 mM) 472 [353] 346 [317] 392 [277] a <0.03

Proinsulin (pmol/L) 5.0 [7.0] 14.5 [12.0] a 7.0 [7.0] a ** <0.0001

a ∂AUC = incremental area-under-curve, expressed as mean incremental concentration between 0 and 8 min following the glucose bolus; ∂AUC

secr = incremental area-under-curve expressed as mean

incremental insulin secretion rate (reconstructed by C-peptide deconvolution); p = p value by Kruskal–Wallis test; a p < 0.0001 vs. NGT and ** p = 0.003 vs. IFG

glucose bolus are signi fi cantly higher in the prediabetic groups, which introduces the need to measure them and adjust the insulin (or C-peptide) changes for the con-comitant changes in glycemia. Second, the interindividual scatter is large and negative numbers are not unusual. Finally, and consequently, the discriminating power across groups is reduced.

Fasting and postprandial plasma glucagon levels have been reported to be abnormal in IFG/IGT, either in absolute value or in the face of the prevailing plasma glucose/insulin concentrations [ 15, 16 ] . Whether this re fl ects an intrinsic a -cell dysfunction or is related to the b -cell dysfunction via a paracrine effect is not clear. Recent pathology data show that the higher proportion of a -cells to b -cells in the islets of some type 2 diabetic subjects is due to a decrease in b -cell number rather than an increase in a -cell number [ 17 ] . In the RISC cohort, fasting hyperglucagonemia is a feature of insulin resistance independently of insulin levels and glucose tolerance [ 18 ] . Likewise, release of GLP-1 and other gastrointestinal hormones is impaired in IFG [ 19 ] and IGT [ 20 ] , again with little information as to whether this secretory incretin defect is primary or secondary to the b -cell dysfunction.

b -Cell Mass

Recent autopsy studies in relatively large groups of subjects have reexamined the question, whether and to what extent there is loss of b -cells in patients with type 2 diabetes [ 21, 22 ] . While both reports concluded that in long-standing diabetes there is an average loss of b -cell volume [ 21 ] or mass [ 22 ] of 40–50%, one study also


found a 50% reduction of b -cell volume in patients labeled as IFG [ 23 ] , whereas the other study concluded that b -cell mass is essentially preserved in patients with recent-onset type 2 diabetes. With all the technical limitations of postmortem exam-inations and the uncertainties about the clinical phenotype and cause of death of the study subjects, the question remains wide open. On the other hand, it is relevant to recall that, in humans undergoing subtotal pancreatectomy (~70%), mild degrees of glucose intolerance are usually the only clinical correlate postsurgery [ 24 ] . The clinical relevance of loss of function viz. loss of mass is best appreciated from lon-gitudinal observations and intervention studies (see below).

Insulin Resistance

As shown in many studies, prediabetes is an insulin resistant state. When assessed by the euglycemic clamp technique (and expressed as the total amount of glucose utilized normalized by fat-free mass as well as steady-state clamp insulin concentra-tions), insulin sensitivity is found to be progressively impaired from NGT to IFG to IGT (Fig. 2.12 ). To emphasize the continuous nature of the relationship between insulin sensitivity and glucose tolerance, Fig. 2.13 shows the regression of insulin sensitivity on the OGTT 2-h plasma glucose concentration adjusted for gender, age, and BMI: all else being equal, insulin sensitivity decreases by 11 m mol/min kg

ffm nM

(or ~10% of the central value in NGT subjects) per each mmol/L increase in 2-h plasma glucose concentrations. Thus, peripheral insulin resistance is an inherent metabolic feature of prediabetes independent of factors—such as sex, age, and obesity—which themselves affect insulin action. Even within the domain of NGT, subjects with higher glucose increments during a standard dynamic test such as the OGTT are more insulin resistant than individuals whose glucose excursions are lower.

Fig. 2.12 Box plots of insulin sensitivity in the NGT, IFG, and IGT group. p Values refer to the comparison with NGT


Importantly, ethnicity may contribute to insulin resistance independent of glucose tolerance and other determinants. In a study employing the insulin clamp technique, Mexican-Americans were shown to be more insulin resistant than non-Hispanic whites regardless of whether they were NGT, IGT, or diabetic [ 25 ] .

The contribution of insulin sensitivity and the dynamic parameters of b -cell function to the plasma glucose concentrations seen at different during a 2-h OGTT can be examined by plotting the correlation coef fi cients linking each control mechanism (insulin sensitivity, glucose and rate sensitivity, and potentiation) to the glucose con-centrations measured at each time-point [ 11 ] . As is evident from the trajectories in Fig. 2.14 , rate sensitivity is prominent early after glucose ingestion, when glucose rises rather rapidly, then wanes; the impact of glucose sensitivity peaks midway but is signi fi cant throughout, insulin sensitivity lags behind glucose sensitivity, and potentiation is only signi fi cant toward the end of the test. These associations are statistical features of the data, but they do shed light on the interplay of insulin secretion and action in shaping the glycemic curve that we interpret as glucose tolerance.

Cause and Evolution of b -Cell Dysfunction in Prediabetes

The cellular mechanisms underlying the glucose “blindness” described above are still uncertain but certainly very complex, and need not be the same in every dysgly-cemic subject. Membrane glucose transport, initial glucose processing by glucokinase, mitochondrial ATP production, generation of intracellular signals such as calcium and c-AMP and associated electrical transduction, and insulin signaling itself each and all are potential sites of inherited or acquired abnormalities [ 2 ] .

Fig. 2.13 Reciprocal association between insulin sensitivity (as the M/I) and 2-h plasma glucose concentration on a standard OGTT. The relation shown by the solid line and its 95% con fi dence intervals is adjusted for center, sex, age, and BMI. Data from the RISC study [ 3 ]


Factors predisposing to the development of prediabetes or to progression from prediabetes to overt type 2 diabetes have been identi fi ed in epidemiological studies. Male sex, a low birthweight, obesity and weight gain, smoking, sedentariness, and a low-quality diet are risk factors in prediabetes [ 15 ] . Interestingly, most if not all of these factors have been shown to affect insulin sensitivity rather than primarily b -cell function [ 15, 26 ] . In contrast, most of the gene variants that have been associ-ated with diabetes—as a phenotype—or glycemia—as a continuous trait—are involved in some aspect of b -cell function [ 27– 32 ] (reviewed in [ 33 ] ). For example, variants in the gene encoding for transcription factor-7-like 2 (TCF7L2), which strongly predicted future diabetes in two independent cohorts, are associated with impaired insulin secretion, incretin effects, and enhanced rate of hepatic glucose production. Furthermore, overexpression of TCF7L2 in human islets reduced glu-cose-stimulated insulin secretion [ 34 ] . Another striking example is the glucokinase mutation identi fi ed in a young girl with severe neonatal hypoglycemia, which was associated with abnormally large islets and a fi vefold decrease in the threshold for glucose-stimulated insulin secretion [ 35 ] . At present, it seems conceivable that a large number of mutations in multiple genes involved in the regulation of b -cell function may constitute the substrate for the predisposition to prediabetes and dia-betes in the general population.

From the pathophysiological standpoint, the two main defects responsible for loss of glucose tolerance—i.e., insulin resistance and b -cell glucose insensitivity—occur together in prediabetes as they do in overt diabetes [ 12 ] , and co-predict inci-dent dysglycemia in NGT subjects [ 36, 37 ] . Thus, despite the fact that defective insulin action can occur in the presence of perfectly preserved b -cell function—as

Fig. 2.14 Partial correlation coef fi cients (with inverted sign, adjusted for sex, age, and BMI) between plasma glucose concentrations during the OGTT and metabolic parameters. Lines are spline functions connecting the coef fi cients of the four metabolic parameters at the fi ve time-points during the OGTT. The gray area includes nonsigni fi cant values for the partial correlation coef fi cients. Adapted from Mari et al. [ 11 ]


is the case of the obese individual with NGT—and, conversely, failing b -cells can cause hyperglycemia in subjects with normal insulin sensitivity—as typi fi ed by well-controlled type 1 diabetes—in human prediabetes, it has not been possible to identify a stage when only one abnormality can be detected. Surrogate measures of b -cell dysfunction and insulin resistance coexist even in children and adolescents at enhanced risk of developing type 2 diabetes [ 38 ] . Furthermore, when IGT or IFG regress to NGT, both insulin resistance and b -cell function improve just as they deteriorate in parallel when IFG/IGT progress to overt diabetes [ 37 ] . The reason(s) for this covariance of physiological functions are imperfectly understood. There may be genetic variants or epigenetic modi fi cations that impact both insulin action and aspects of b -cell function. Another possibility is insulin resistance of b -cells: like classical target tissues, b -cells are richly endowed with insulin receptors. When b -cell insulin receptors are selectively knocked out, some of the transgenic mice develop hyperglycemia with defective b -cell glucose sensing [ 39, 40 ] . Conversely, in healthy volunteers pre-exposure to high physiological hyperinsulinemia potenti-ates insulin release in response to intravenous glucose [ 41 ] . These fi ndings have led to the hypothesis that insulin resistance in the b -cell synergizes with insulin resis-tance in the periphery to produce the two classic defects of diabetes/prediabetes [ 42 ] . More work is needed to produce a complete proof of this predicament.

Conclusions

There appears to be little doubt that prediabetes is characterized by a loss of b -cell function qualitatively similar to that of overt type 2 diabetes but of a lesser severity. It has been argued that b -cell dysfunction is more severe in IFG while insulin resistance is more marked in IGT [ 43, 44 ] ; the opposite has also been claimed [ 45 ] . The arbitrary nature of diagnostic thresholds (e.g., IFG de fi ned as a fasting glucose between 6.1–6.9 and 5.7–6.9 mmol/L) viz. the continuous nature of physiological functions (cf, Figs. 2.10 and 2.13 ) may well explain the divergent results obtained in small-size clinical studies or in datasets of surrogate measures. Given the tight dependency of fasting glucose levels on endogenous glucose output [ 46 ] , it is obvious that picking subjects with a higher fasting glucose will also select for more severe hepatic insulin resistance, possibly linked with a low pre-hepatic insulin-to-glucagon ratio. By the same token, extracting subjects with low fasting but high post-OGTT glucose levels will bias the results toward insulin resistance. In fact, any mix of b -cell dysfunction and insulin resistance can be predicted by variably combining the glucose levels in Fig. 2.14 . Along the same line of reasoning, the literature is replete with analyses of predictivity of individual plasma glucose concentrations, fasting and post-OGTT [ 47 ] . In reality, both values carry independent predictive power [ 1 ] as a result of the partially different underlying physiological mechanisms.

What is clinically more relevant to recall is that the glucose abnormalities are part of a constellation of subclinical abnormalities that consistently occur together in prediabetic individuals. In comparison with NGT controls, IFG/IGT subjects


have a higher family history of diabetes, are slightly more often men than women, somewhat older, de fi nitely heavier, and with a more central distribution of body fat; values of heart rate, systolic and diastolic blood pressure are higher as are serum lipid levels (LDL-cholesterol, triglycerides, and FFA) while HDL cholesterol con-centrations are lower [ 48 ] . The clustering also suggests that insulin resistance/hyperinsulinemia may link diabetes with clinical hypertension and dyslipidemia either mechanistically or by genetic linkage (or both). Of further note is that recent work has emphasized that the prediabetic phenotype is closely predictive of nonal-coholic fatty liver disease [ 49 ] .

In summary (Fig. 2.15 ), prediabetes encompasses conventional diagnostic cate-gories of IFG and IGT, but really is a bandwidth of glucose concentrations and a temporal phase over a continuum extending from conventional NGT to overt type 2 diabetes. Insulin resistance and defective glucose sensing at the b -cell are the cen-tral pathophysiologic determinants, with insulin hypersecretion acting as a compen-satory mechanism. While genetic in fl uences impact on b -cell function, becoming overweight is the main acquired challenge to insulin action. However, there may be inherent genetic components that bring together insulin resistance and b -cell dys-function in the same individual, thereby signaling his/her predisposition to progres-sion (asterisks in Fig. 2.15 ). Treatment of high glucose levels by whatever means (lifestyle intervention, hypoglycemic agents, bariatric surgery) is accompanied by recovery of b -cell function, typically rapid and occasionally complete. This phe-nomenon constitutes incontrovertible evidence that b -cells in dysglycemic states are stunned but mostly alive [ 50 ] . This forms the rationale for early and vigorous treatment of any degree of dysglycemia if the b -cell demise characterizing long-standing diabetes is to be prevented.

Fig. 2.15 Schematic representation of the natural history of b -cell function and insulin sensitivity. See text for further explanation


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prevention of type 2 diabetes || pathophysiology: loss of β-cell function

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