Doi:10.1016/s0140-6736(08)60736-9

Intensive insulin therapy in newly diagnosed type 2 diabetes
The natural history of type 2 diabetes is characterised sustained euglycaemia (ie, off any antidiabetic therapy) See Editorial page 1723
by worsening hyperglycaemia and progressive in patients with type 2 diabetes.6–9 The “remission” of See Articles page 1753
deterioration in function of the insulin-secreting type 2 diabetes achieved in these studies persists for
pancreatic β cells.1 Despite intense investigative 1 year after the cessation of insulin therapy in about
eff orts, the pathophysiological basis underlying β-cell 40% of patients. Furthermore, Li and colleagues6
dysfunction (and the concomitant loss of β-cell mass) reported that patients who maintained euglycaemia off
remains unclear. Nevertheless, the central importance antidiabetic therapy for 1 year showed greater recovery
of declining β-cell function in type 2 diabetes is of β-cell function than their counterparts, when assessed
underscored by its correlation with a progressive loss immediately after 2 weeks of continuous subcutaneous
of glycaemic control, which typically occurs over time.2,3
infusion.6 The suggestion has therefore been made that Although β-cell dysfunction contributes to worsening an improvement in β-cell function, especially restoration glycaemia, hyperglycaemia itself further undermines of fi rst-phase insulin secretion, might be responsible β-cell function. This so-called glucotoxicity is apparent for the ability of intensive insulin therapy to induce in the observation that the fi rst-phase component of sustained euglycaemia.
normal biphasic insulin secretion is abolished when In today’s Lancet, Jianping Weng and colleagues10 the blood glucose concentration exceeds 6·4 mmol/L.4 extend these concepts by reporting a randomised trial Accordingly, early in the course of type 2 diabetes (ie, that compares the eff ects of temporary (2–5 weeks) when suffi cient residual β-cell mass still exists), the intensive insulin therapy (continuous subcutaneous glucose-lowering eff ect of antidiabetic therapy can be infusion or multiple daily injections) versus oral amplifi ed by improved endogenous insulin secretion antidiabetics (ie, metformin, gliclazide, or, in most secondary to the elimination of hyperglycaemia. patients, both) on remission of diabetes and β-cell Unfortunately, however, this eff ect is ultimately function in 382 newly-diagnosed patients with type 2 transient, because no oral antidiabetic agent has yet diabetes in nine centres in China. Glycaemic control was been shown to profoundly change the inexorable rapidly achieved (mean 7·9 days [SD 4·6]) in 92·1% of β-cell deterioration and worsening glycaemia in type 2 patients. When assessed 2 days after stopping therapy, diabetes.5 fi rst-phase insulin secretion (measured by acute insulin Insulin therapy is usually instituted late in the response on an intravenous glucose-tolerance test) course of type 2 diabetes, when glycaemic control was signifi cantly increased with all three regimens. can no longer be maintained with oral antidiabetics. Importantly, remission at 1 year after therapy was Interestingly, however, as shown in limited studies up signifi cantly higher in the insulin groups (continuous to now (table), early implementation of a short course infusion, 51·1%; multiple injections, 44·9%) than in the of intensive insulin therapy by continuous subcutaneous oral antidiabetic group (26·7%). Moreover, in patients insulin infusion or multiple daily injections can induce in remission, the decline in the acute insulin response Mean age Mean body-mass Duration of type 2
Baseline
Duration of
Patients who achieved Patients with
Patients with
index (kg/m²)
diabetes
therapy (days)
euglycemia with
euglycemia at
euglycemia at
therapy (%)
6 months (%)
1 year (%)
NA=not available. CSII=continuous subcutaneous insulin infusion. MDI=multiple daily injections. OAD=oral antidiabetic agent.
Table: Previous studies of insulin therapy
www.thelancet.com Vol 371 May 24, 2008
over 1 year in the insulin groups did not reach statistical Furthermore, an increased mechanistic understanding signifi cance, whereas the group on oral antidiabetics of the specifi c eff ects of early insulin therapy on the showed a signifi cant decrease in this response over the survival and function of β cells over time might provide same period, suggesting that preservation of fi rst-phase new insights into the pathophysiology of progressive insulin secretion probably contributed to the greater β-cell deterioration in type 2 diabetes.
remission achieved with either insulin regimen.
Although certain limitations of this study need to be Ravi Retnakaran, *Daniel J Drucker noted (including: limited description of β-cell function Banting and Best Diabetes Centre (DJD) and Division of and glycaemic control during the year; absence of clinical Endocrinology (RR, DJD), University of Toronto, Toronto, ONT, Canada M5G 1X5; and Leadership Sinai Centre for Diabetes (RR) characterisation of the remission and non-remission and Samuel Lunenfeld Research Institute(DJD), Mount Sinai groups at 1 year; and the single ethnic group under study), these fi ndings are intriguing. In particular, the comparison of intensive insulin and oral therapy is an important novel RR receives research support from Merck. DJD has served as an adviser for or feature of this trial, because earlier studies only assessed consultant to Amylin Pharmaceuticals, Arisaph Pharmaceuticals, Conjuchem, Eli Lilly, Emisphere Technologies, GlaxoSmithKline, Glenmark Pharmaceuticals, Isis continuous insulin infusion or multiple daily injections. Pharmaceuticals, Merck Research Laboratories, Novartis Pharmaceuticals, Novo Indeed, although both insulin and oral drugs lowered Nordisk, Phenomix, Takeda, and Transition Pharmaceuticals. DJD also receives research support from Merck and Novo Nordisk.
glucose concentrations, the apparent benefi cial eff ect of 1 Kahn SE. The relative contributions of insulin resistance and beta-cell intensive insulin therapy on remission and preservation dysfunction to the pathophysiology of type 2 diabetes. Diabetologia 2003;
46: 3–19.
of fi rst-phase insulin secretion suggests that other factors Matthews DR, Cull CA, Stratton IM, et al, for the UKPDS Group. beyond the elimination of glucotoxicity might be relevant. Sulphonylurea failure in non-insulin dependent diabetic patients over
6 years (UKPDS 26). Diabetic Med 1998; 15: 297–303.
In this context, insulin therapy would be expected 3 UKPDS Group. Overview of 6 years’ therapy of type 2 diabetes: a to decrease the secretory demand for endogenous progressive disease (UKPDS 16). Diabetes 1995; 44: 1249–58.
Brunzell JD, Robertson RP, Lerner RL, et al. Relationships between fasting insulin placed on the β cells (by contrast with the β-cell plasma glucose levels and insulin secretion during intravenous glucose
tolerance tests. J Metab 1976; 42: 222–29.
stimulatory eff ect of the sulphonylurea gliclazide, which 5 Turner RC, Cull CA, Frighi V, et al, for the UKPDS Group. Glycemic control most patients in the oral-antidiabetic group received). As with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies such, these data might support the concept of a benefi cial (UKPDS 49). JAMA 1999; 281: 2005–12.
eff ect of “β-cell rest” with insulin therapy.
Li Y, Xu W, Liao Z, et al. Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients is associated with improvement of Alternatively, other biological actions of insulin might β-cell function. Diabetes Care 2004; 27: 2597–602.
be contributory, including anti-infl ammatory activity Ilkova H, Glaser B, Tunckale A, Bagriacik N, Cerasi E. Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients by transient and the potential direct eff ects of insulin-receptor intensive insulin treatment. Diabetes Care 1997; 20: 1353–56.
signalling on β-cell growth and survival. Although 8 Park S, Choi SB. Induction of long-term normoglycemia without medication in Korean type 2 diabetes patients after continuous subcutaneous insulin the relevant biological mechanisms and target tissues infusion therapy. Diabetes Metab Res Rev 2003; 19: 124–30.
Ryan EA, Imes S, Wallace C. Short-term intensive insulin therapy in newly contributing to preferential improvement in β-cell diagnosed type 2 diabetes. Diabetes Care 2004; 27: 1028–32.
function remain unclear, these data suggest that the 10 Weng J, Li Y, Xu W, et al. Eff ect of intensive insulin therapy on β-cell function and glycaemic control in patients with newly diagnosed type 2 use of intensive insulin therapy early in the course of diabetes: a multicentre randomised parallel-group trial. Lancet 2008; type 2 diabetes warrants further clinical investigation. 371: 1753–60.
Novel cardiac therapies and innocent bystanders
See Articles page 1761
The oxidation hypothesis of atherosclerosis is an randomised trials of antioxidant (principally vitamin) attractive explanation of why high concentrations of therapy have shown cardiovascular benefi t.2 This lack LDL cholesterol result in ischaemic cardiovascular events of positive fi ndings might be because the antioxidants in some, but not all, individuals. This theory is supported have been started too late in the disease process, because by several large epidemiological studies suggesting an there is no accurate, readily available test that facilitates inverse association between the intake of antioxidant targeting treatment to those with increased oxidative vitamins and cardiovascular events.1 However, no stress, or because antioxidant vitamins are not potent www.thelancet.com Vol 371 May 24, 2008

Source: http://www.dangin.co.kr/pdf/T2DM_INSULIN_Comment.pdf