Acute Sulfonylurea Therapy at Disease Onset Can Cause Permanent Remission of KATP-induced Diabetes

Maria Sara Remedi; Sophia E. Agapova; Arpita K. Vyas; Paul W. Hruz; Colin G. Nichols


Diabetes. 2011;60(10):2515-2522. 

In This Article

Abstract and Introduction


Objective—Neonatal diabetes mellitus (NDM) can be caused by gain-of-function ATP-sensitive K+ (KATP) channel mutations. This realization has led to sulfonylurea therapy replacing insulin injections in many patients. In a murine model of KATP-dependent NDM, hyperglycemia and consequent loss of β-cells are both avoided by chronic sulfonylurea treatment. Interestingly, KATP mutations may underlie remitting-relapsing, transient, or permanent forms of the disease in different patients, but the reason for the different outcomes is unknown.
Research Design nd Methods—To gain further insight into disease progression and outcome, we examined the effects of very early intervention by injecting NDM mice with high-dose glibenclamide for only 6 days, at the beginning of disease onset, then after the subsequent progression with measurements of blood glucose, islet function, and insulin sensitivity.
Results—Although ~70% of mice developed severe diabetes after treatment cessation, ~30% were essentially cured, maintaining near-normal blood glucose until killed. Another group of NDM mice was initiated on oral glibenclamide (in the drinking water), and the dose was titrated daily, to maintain blood glucose <200 mg/dL. In this case, ~30% were also essentially cured; they were weaned from the drug after ~4 weeks and again subsequently maintained near-normal blood glucose. These cured mice maintain normal insulin content and were more sensitive to insulin than control mice, a compensatory mechanism that together with basal insulin secretion may be sufficient to maintain near-normal glucose levels.
Conclusions—At least in a subset of animals, early sulfonylurea treatment leads to permanent remission of NDM. These cured animals exhibit insulin-hypersensitivity. Although untreated NDM mice rapidly lose insulin content and progress to permanently extremely elevated blood glucose levels, early tight control of blood glucose may permit this insulin-hypersensitivity, in combination with maintained basal insulin secretion, to provide long-term remission.


It is now clear that a large proportion of neonatal diabetes mellitus (NDM) can be accounted for by mutations in the KCNJ11 and ABCC8 genes that encode the Kir6.2 and sulfonylurea receptor 1 (SUR1) subunits of the ATP-sensitive K+ (KATP) channel in pancreatic β-cells.[1–9] Increased glucose metabolism leads to elevated intracellular [ATP]:[ADP], which normally closes KATP channels, leading to membrane depolarization, Ca2+-entry, and triggering of secretion.[10,11] NDM mutations invariably result in reduced channel sensitivity to ATP inhibition, KATP channel overactivity, decreased membrane excitability, and reduced insulin secretion.[12]

Interestingly, in most NDM cases, the disease is permanent NDM (PNDM), requiring lifelong therapy, but in the remainder, the disease is transient NDM (TNDM), spontaneously remitting within weeks or months of diagnosis, but typically relapsing around puberty or later in life.[13–16] It is of note that either outcome can be obtained with the same KATP mutation. Members of the same family carrying the same KATP channel mutation show different disease outcomes ranging from TNDM to PNDM and even late-onset diabetes and gestational diabetes.[15–19] This indicates variable penetrance of the molecular defect and leads us to speculate that the disease outcome might depend not only on additional genetic or epigenetic factors, but also on the timing of diagnosis and the nature of the therapeutic intervention.

Predicting the human disease, we previously developed transgenic mice constitutively expressing ATP-insensitive β-cell KATP channels.[20] These mice developed profound neonatal diabetes and died shortly after birth, precluding detailed analysis of disease progression. We subsequently generated inducible KATP gain-of-function (GOF) transgenic mice by insertion of an ATP-insensitive Kir6.2 construct into the Rosa26 locus, under Cre-recombinase control.[21] By crossing with tamoxifen-inducible Pdx1PBCreERTM (Pdx-Cre)[22] mice, we generate β-cell–specific (although PDX1 promoters could alter gene expression in the brain[23]) conditional Pdx-Cre/Rosa26-Kir6.2[K185Q,ΔN30] double transgenic (DTG) mice that develop severe glucose intolerance within 2 weeks after tamoxifen injection and progressively severe diabetes.[21] Although these mice subsequently survive with uncontrolled blood glucose (>600 mg/dL), they secondarily develop profound loss of β-cell mass and dramatic reduction of insulin content.[21] It is noteworthy that diabetes and the secondary progression of the disease are completely avoided by maintenance of normoglycemia, achieved either by syngeneic islet transplantation or by implantation of slow-release sulfonylurea (SU) pellets before disease onset.[21] Diabetes can be completely avoided in each case, but in the first case this is because of insulin secretion from the transplanted islets and, in the second, because constitutive inhibition of KATP ensures persistent depolarization of endogenous β-cells,[24] and hence endogenous insulin secretion.[21]

In human NDM, it is now quite clear that SU therapy can successfully control blood glucose levels and avoid (or reduce) insulin requirements in the majority of KATP-induced PNDM[15,25–27] and also in TNDM.[28–31] As a preferable alternative to lifelong exogenous insulin injections, SU drugs circumvent the metabolic signal in the β-cell by directly targeting KATP overactivity to restore endogenous insulin secretion. This effect can also be augmented in the presence of potentiating hormones (glucagon and glucagon-like peptide 1 [GLP-1]) and by other so-called KATP-independent mechanisms; thus insulin secretion becomes quasi-physiological and may maintain stable glycemia. SU requirements are quite variable. Successful therapeutic response in NDM patients frequently requires larger SU doses than the current recommended regimen for adult patients with type 2 diabetes,[25,26] and in some cases SU have proved to be ineffective and the patients continue to require maintained insulin therapy.[19,26,32] Paralleling these findings, and potentially explaining nonresponsivity to SU, we found that late-onset SU pellet treatment of mice with severe diabetes (glucose >300 mg/dL) was ineffective, presumably because the profound loss of β-cells had already occurred.[21]

Controlled studies of drug therapy in human NDM are not practically feasible, and so, in the current study, we have explored the treatability of NDM by SU drugs after disease induction in DTG mice. The results indicate that there is a critical window early in the disease during which compensatory mechanisms may develop, switching the disease from a permanent, progressively worsening diabetes to a transient hyperglycemia with subsequent long-term remission. These striking results may have important implications for understanding human NDM progression and therapeutic possibilities.


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