The Present and Future of Insulin Therapy in the Era of Pathophysiologic Treatment Of

The Present and Future of Insulin Therapy in the Era of Pathophysiologic Treatment of T2DM:Marked Reduction of the Need for Insulin Use in T2DM

In the past 1-2 decades, the teaching has been that many/ most patients with Type 2 Diabetes will require

insulin therapy during the course of their life with the illness. Moreover, in many, early insulin therapy has been advised to reduce gluco-toxicity and lipo-toxicity, eg: to preserve beta-cell function and mass. In those failing non-insulin therapy, non-insulin agents are frequently/ usually stopped as basal insulin is begun and titrated ,and in some 80% of those with fasting sugars under control, fast analog insulin is required to control post-prandial /pre-meal, pre-sleep values. (1?)However, in attempt to reach ADA (2) or AACE (3) glycemic goals, hypoglycemia and weight gain are frequent complications of our current approaches. (4a, 4b). We especially note that some 87% of hypoglycemia is due to fast-analog use in type 2 diabetes (5 ). Though in well-monitored research trials such as the UKPDS (6) , a micro and macrovascular benefit accrued from attempts to get to HgA1c of 7.0, in the ‘real world‘, there is a marked increase in risk of dying 1 year after starting insulin therapy (7,8). And even in well-experienced hands , aiming for HgA1c of 6.0 resulted in benefits of microvascular complications, but no CV or mortality benefit ,ADVANCE, VADT, (9,10) , and in the ACCORD trial (11) no CV benefit and an increased mortality. Though there is reasonable debate on the role of hypoglycemia in these negative results (12), most agree that hypoglycemia , directly or indirectly, possibly through effects of weight gain, was a cause for these negative trials. (13, 14, 15)In this paper, we suggest that with the advent of the multiple non-insulin agents for the therapy of Type 2 diabetes, often multiple agents used in combination to treat the multiple pathophysiologic causes of hyperglycemia (16), the logic for early use of insulin is no longer operative/ necessary, many patients who may have ‘needed’ insulin in past do not/ will not need insulin in the future, and that the vast majority of patients that might still need basal insulin will not require bolus insulin. Normal Metabolism and Patho-physiology of Type 2 Diabetes. In normal metabolism, the classic bi-hormonal hypothesis (17) describes increased secretion of insulin from the beta cell and suppression of glucagon from the alpha cell when eating, resulting in metabolism and storage of nutrients in glucose sensitive tissues while suppressing hepatic glucose production , and the opposite during periods of food lack, resulting in hepatic gluconeogenesis and glycogenolysis, reduced peripheral glucose uptake, in order to provide enough glucose for brain function. In addition, Incretin secretion from the gut potentiates the normal insulin/ glucagon responses to eating. (18) Insulin release is characterized by a finally-tuned ‘perfectly-modulated’ glucose-sensing and insulin-secretory mechanism (including paracrine and CNS mediated signals to beta-cells- anticipatory insulin sectretion) causing a ‘perfect match’ of glucose entrance/disposal from the blood, resulting in ‘normal’ glycemia. The insulin is secreted into the portal system, ie: directly to the liver, to maximixe its storing glucose and other metabolic effects in the liver, and minimizing peripheral insulin concentrations to the ‘correct’ amount in order to achieve appropriate peripheral glucose uptake in insulin-sensitive tissues, avoiding hypoglycemia and avoiding ‘receptor –desensitization’ resulting in insulin resistance. (19 ?)Type 2 diabetes, (in a pathophysiologic description of the multiple causes of hyperglycemia which has implications on therapeutics), is a strongly genetic disease, where one inherits genes related to both insulin resistance ( at the liver, muscle and adipose tissue) , and islet cell dysfunction ( decreased insulin secretion, decreased incretin effect and lack of glucagon suppression)( 20,21,22,23) There is also fast gastric emptying, resulting in a rapid rise in post-meal hyperglycemia, there's a central mechanism of increased insulin resistance generated a lack of dopamine rise in the superchiasmic nucleus in early morning, resulting in increased peripheral insulin resistance and sympathetic tone,

and lastly, it's been recently recognized that there is increased glucose reabsorption at the kidney, potentiating existing hyperglycemia. (16) Insulin resistance alone is insufficient to cause diabetes,(24?) But if one has genes that prevent the beta-cell from compensating with sufficient insulin release, eg: beta-cell dysfunction, then one presents with pre-diabetes and ultimately overt T2DM.[ 16 ,25,26,27.] Abnormal b-cell function starts early, often years before even one is discovered to have pre-diabetes, with loss of first-phase insulin secretion ( patients present with late post-prandial hypoglycemia) [ 28.]. It progresses to pre-diabetes (IFG or IGT- presentation dependent, within any one patient , on some combination of hepatic vs peripheral insulin resistance and first or first-and-second phase insulin release deficiencies) (28a, 28b) . At diagnosis of overt T2DM , beta cell function is reduced [29] and Defronzo calculates decreased beta cell function of up to 80% (30a, 30b), and beta-cell mass (measured as mass or volume-albeit they are not the same thing) is estimated to be reduced ~20% [31-35], and up to 43% [36]. Both are superficially spoken about as being progressively reduced even further, over time, ie: the ‘natural history’ of T2DM, with rapid decrements of beta cell function ~18%/ year after diagnosis (37), and loss of beta-cell mass of 63% at time of death (36)

A major concept in this regard is the contribution of both glucotoxicity and lipotoxicity to the continued and further decrement in beta cell function.. [38,39.]. Implications of this are that insulin should even be used early in the ‘natural history’ of the disease to reduce gluco and lipo-toxicity (40-45)

at least in part improving HOMA-IR early in DM [ 46] ,and it may allow patients to get off insulin and use other therapies.[ 47-50]. However, the strong implications are that many/most patients withT2DM will continue to take insulin and be perceived to REQUIRE insulin therapy, , both basal and then bolus, , and, that once on insulin, it is usually a permanent requirement.( 51. ) However, 2 major principles are coming to the fore in recent discussions. The first is that we may be overestimating the loss of beta cells in T2DM (52). A proportion of beta-cells in type 2 diabetic islets may not be detectable by standardimmunohistochemistry staining, possibly due to insulin degranulation,potentially leading to an overestimation of beta-cell loss, in at least some type 2 diabetic pancreases or islets. Moreover, basic physiology/ pathology courses teach that >80% of pancreas must be removed to cause hyperglycemia [53?], and one can argue that this doesn’t happen in many/ most patients given our experience with bariatric surgery. That is, many/most patients with long durations of diabetes , on decades of insulin therapy , who undergo bariatric procedures lose their need for all medications , including insulin, within days of their procedure, before significant weight loss occurs. [54]. These observations imply that loss of mass is slower than the current general impression believes. In addition , it can be taken to imply that loss of mass, b-cell failure may be slowed, preserved and maybe even reversed to some degree by life style and some of the current medications in our quiver (39). For example we know beta-cell dysfunction ( and possibly reductions in beta-cell mass) can be improved/ reversed with TZD[55,56,57,63-66], GLP-1 RA[58,59,60] eg: 3.5 yr. durability with exenatide [[61]. Life-style changes , in Daqing, (67 ?)DPP-2 trials (68?), showed reductions in progression to overt diabetes of ~60%. In the DPP-2 trial incidence to progression to DM was reduced from ~10%/year to ~ 5% / year. And in DPP-2 X % were able to be reveresed to Hga1c levels <5.7 , ie normal, reducing future risk of overt T2DM to only ~3%/year. (69?)Pharmacologic therapy with acarbose , metformin, all reduce rate of progression to overt DM.( 62,63)And recently DeFronzo in a pilot study showed increased reversal to NGT with 2 (metformin/pioglitazone) and, to a greater degree with 3 drug (metformin/pioglitazone / exenatide ) combination therapy (70) and GLP-1 can revert IGT to nml. [ 71,72)Thus, we submit, an altered or even new paradigm of the ‘natural history ‘ of diabetes be considered. The genetic abnormalities associated with early loss of mass and resultant decreased beta cell function is slow in most , with the age of phenotypic expression of these abnormalities , ie dx of DM, dependent on which genetic abnormalities exist (including inflammatory destruction of beta-cells) , age of appearance of the environmentally based factors causing maximal insulin resistance, and reversible / modifiable factors, such as glucose and lipotoxicity that can accelerate (or decelerate) abnormal beta-cell function at any point in time.This paradigm carries with it implications for a new therapeutic approach that fits with Defronzo’s pathophysiologic approach to diabetes care [16). That is, with the appropriate use of known, existing, available therapeutic modalities (lifestyle and pharmacologic) we can clearly alter the ‘natural history’ of T2DM, modify the implied inexorable loss of beta-cell function/mass, such that many/most patients with T2DM don’t need insulin therapy, and of those that need basal therapy, most will not need bolus therapy. MY PHILOSOPHY