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.comVol 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.comVol 371 May 24, 2008
Shun Lee Catholic Secondary School Biology (S6) Scheme of work (2011/2012) Laboratory safety and evacuation Level Test Summer Tutorial Class ( 37 periods/~22 hours) Bk E1 Ch 1 Regulation of water content Time allocation Learning target Practical Assignment Exercise Teaching resources (No. of periods) 1.1 Importance of • To identify the m
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